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Endocrine Reviews 22 (1): 2-35
Copyright © 2001 by The Endocrine Society

POU Domain Factors in the Neuroendocrine System: Lessons from Developmental Biology Provide Insights into Human Disease1

Bogi Andersen and Michael G. Rosenfeld2

Division of Endocrinology and Metabolism (B.A.), and Howard Hughes Medical Institute (M.G.R.), Department of Medicine, University of California, San Diego, La Jolla, California 92093-0648


    Abstract
 Top
 Abstract
 I. Introduction
 II. Structure and...
 III. Development of the...
 IV. Expression and Function...
 V. Relevance of POU...
 References
 
POU domain factors are transcriptional regulators characterized by a highly conserved DNA-binding domain referred to as the POU domain. The structure of the POU domain has been solved, facilitating the understanding of how these proteins bind to DNA and regulate transcription via complex protein-protein interactions. Several members of the POU domain family have been implicated in the control of development and function of the neuroendocrine system. Such roles have been most clearly established for Pit-1, which is required for formation of somatotropes, lactotropes, and thyrotropes in the anterior pituitary gland, and for Brn-2, which is critical for formation of magnocellular and parvocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus. While genetic evidence is lacking, molecular biology experiments have implicated several other POU factors in the regulation of gene expression in the hypothalamus and pituitary gland. Pit-1 mutations in humans cause combined pituitary hormone deficiency similar to that found in mice deleted for the Pit-1 gene, providing a striking example of how basic developmental biology studies have provided important insights into human disease.

I. Introduction

II. Structure and Transcriptional Function of POU Domain Factors

A. DNA-binding sites for POU domain factors

B. Protein chemistry

C. Protein-protein interactions

D. Mechanisms of transactivation

III. Development of the Hypothalamo-Pituitary Region

IV. Expression and Function of POU Domain Factors in the Neuroendocrine System

A. Pit-1

B. Oct-1

C. Oct-2

D. Overview of expression of Brn-1, Brn-2, Brn-4, and Tst-1 in the neuroendocrine system

E. Brn-2

F. Brn-4

G. Tst-1

H. Oct-3

I. Brn-5 and RPF-1

V. Relevance of POU Domain Factors to Diseases of the Neuroendocrine System

A. Pit-1 mutations as a cause of combined pituitary hormone deficiency in humans

B. Brn-4 mutations in humans

C. Potential implications for other diseases.


    I. Introduction
 Top
 Abstract
 I. Introduction
 II. Structure and...
 III. Development of the...
 IV. Expression and Function...
 V. Relevance of POU...
 References
 
THE ACRONYM POU (pronounced pow) is derived from the names of three mammalian transcription factors, the pituitary-specific Pit-1 (1, 2), the octamer-binding proteins Oct-1 (3) and Oct-2 (4, 5, 6, 7), and the neural Unc-86 from Caenorhabditis elegans (8). These initial members of the POU gene family, as well as subsequently discovered members, are characterized by a unique bipartite DNA-binding domain referred to as the POU domain (9). This domain is composed of a variant homeodomain (POU-H), which is linked via a nonconserved linker to another conserved domain referred to as the POU-specific (POU-S) domain. Both subdomains contain helix-turn-helix motifs that directly associate with the two components of bipartite DNA-binding sites (Fig. 1Go).



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Figure 1. The three-dimensional structure of the Pit-1 POU domain bound to DNA compared with the Oct-1 POU domain bound to an octamer site. Pit-1 binds as a dimer to a palindromic PRL-related DNA site with the POU-S and POU-H domains of each monomer binding to the same side of DNA (left panel). The third helix of both subdomains makes major groove contacts. For comparison, the schematic on the right represents the different organization of Oct-1 bound to an octamer site where the two subdomains bind on the opposite sites of DNA and the Oct-1 POU-S domain (shown in yellow) has a flipped orientation compared with the Pit-1 POU-S domain (shown in pink).

 
While highly homologous in the POU domain, the genes expressing the various POU domain factors are distributed on several different chromosomes, not clustered like the Hox genes (10, 11, 12, 13, 14, 15, 16, 17, 18, 19). POU domain genes have been described in organisms as divergent as C. elegans (20), Drosophila (21, 22, 23), Xenopus (24), zebrafish (25, 26), and humans, but have not yet been identified in plants or fungi. In all species these genes seem to carry out essential functions for organ development and cellular differentiation.

Although some general conclusions can be reached about POU domain factors, more importantly the various members serve a wide variety of functions during development. In fact, it is reasonable to predict that an individual POU factor may play multiple distinct roles in those organs in which it is expressed during development and in the adult. There is evidence for the role of POU domain factors in inhibition and promotion of cell proliferation and determination of cell lineages, as well as in regulation of cell migration, survival, and terminal differentiation. Because of their overlapping expression patterns and similar DNA-binding preferences, POU factors coexpressed in a single organ may be functionally redundant. In addition to a role in early and late development, members of this family play roles in physiological regulation of gene expression in the adult. While POU domain genes are expressed in all organ systems, this review focuses on the role of POU domain factors in the neuroendocrine system with special emphasis on the hypothalamo-pituitary axis.

A great deal of knowledge has accumulated about the biological function of POU domain factors since their initial identification in 1988. In addition to insightful in vitro experiments, progress in this field has been greatly facilitated by the ability to create targeted mutations of POU domain genes in the mouse. These studies, as well as the discovery of human disease mutations involving the POU domain factor Pit-1, have established a crucial role for POU domain factors in neuroendocrine development and function.

The 15 known mammalian POU domain genes have been classified into six different groups based on homology in the POU domain region, including the nonconserved linker region (Table 1Go). The class I POU factor, Pit-1 (GHF-1), is required for the generation and maintenance of three different cell types in the anterior pituitary gland of humans and other mammals (1, 2, 27). Expression analyses and in vitro biochemical/molecular biology experiments have implicated the octamer-binding proteins Oct-1 and Oct-2, which belong to class II POU domain factors, in neuroendocrine function and development (28, 29, 30, 31). The third class II factor, Skn-1a, is selectively expressed in epidermis and has no role in the neuroendocrine system (32, 33, 34, 35). The class III POU domain subgroup consists of four closely related factors, Brn-1, Brn-2, Brn-4, and Tst-1/Oct-6/SCIP, which are all encoded by intronless genes (36). For members of this subgroup, a role in neuroendocrine development has been most clearly established for Brn-2, which is required for the formation of hypothalamic nuclei and the posterior pituitary gland (37, 38). The other class III POU factors may also play a crucial role in neuroendocrine function and development. Brn-3 and two other members of the class IV POU factors have been shown to be important for various aspects of sensory development, but have no known roles in the neuroendocrine system and will not be further discussed in this review (39, 40, 41, 42, 43, 44, 45, 46, 47, 48). The class V POU factor Oct-3 (Oct-4) is expressed in germ cells, embryonic stem cells, and in early neurogenesis where its down-regulation may be crucial for proper neural formation (49, 50, 51, 52, 53). Sprm-1, the second class V factor, is selectively expressed in spermatocytes and has no role in the neuroendocrine system (54, 55). The class VI POU factor Brn-5 is widely distributed and highly expressed in hypothalamic regions (56, 57, 58). The other class VI member, retina-derived POU-domain factor-1 (RPF-1), is expressed in the retina, the medial habenula, and in dispersed populations of neurons in the dorsal hypothalamus (59).


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Table 1. Mammalian POU domain factors

 
In addition to reviewing the demonstrated or proposed roles for POU domain factors in the neuroendocrine system, we will summarize aspects of the basic molecular biology of POU factors. Extensive investigations into the biochemistry and molecular biology of POU domain factors have given insights into structure-function aspects such as DNA binding, protein-protein interactions, and mechanisms of transcriptional regulation. While many of these studies involve the action of POU domain factors outside the neuroendocrine system, they are informative and likely to provide leads regarding the mechanisms of action for POU domain factors in the neuroendocrine system.


    II. Structure and Transcriptional Function of POU Domain Factors
 Top
 Abstract
 I. Introduction
 II. Structure and...
 III. Development of the...
 IV. Expression and Function...
 V. Relevance of POU...
 References
 
A. DNA-binding sites for POU domain factors
While POU domain factors exhibit a surprising flexibility in DNA binding (60, 61), a general rule has emerged suggesting that high-affinity binding sites are often bipartite with each "half-site" contacting either the POU-S or the POU-H domain (Fig. 1Go) (62, 63). This principle has been elegantly demonstrated for the interaction of Oct-1 with an octamer site (ATGCAAAT) where the POU-S domain and the POU-H domains associate with the ATGC- and AAAT-parts, respectively (64, 65, 66). The spacing and orientation between the two halves of a binding element can vary, and the ability of different POU domain factors to recognize such sites depends in part on the length, sequence, and flexibility of the linker tethering the POU-S and POU-H domains (63, 67). In addition, there is evidence that diversity in the POU DNA binding may stem, in part, from amino acid-base interactions that are more flexible than those observed for classical homeodomains (62).

Often, high-affinity binding sites for POU factors are flanked by lower affinity binding sites that are capable of promoting cooperative DNA binding of POU factor dimers. These "second" sites are usually highly diverged from high-affinity binding sites and may contain isolated A/T-rich regions or the POU-S recognition sequence ATG (CAT on the opposite strand). In this section, we will first review the DNA binding characteristics of different POU domain factors, and then summarize the main conclusions from the collection of studies on this issue.

1. DNA binding sites for the class I factor Pit-1. Pit-1 was originally identified based on its ability to bind to multiple sites in the regulatory regions of its target genes GH and PRL (1, 2). Similar Pit-1 binding sites have been described in the regulatory regions of several other pituitary-expressed genes that are likely targets of Pit-1. These include the Pit-1 gene itself (68, 69, 70), the TSH{beta} gene (71, 72, 73), the rat and human GHRH receptor gene-regulatory regions (74, 75), the rat somatostatin receptor 1 gene-regulatory region (76, 77), and the human TRH receptor gene-regulatory region (78). These sites, which vary widely around the consensus sequence ATGNATA(A/T)(A/T)(A/T), tend to be found in multiples in Pit-1 target genes (Table 2Go). On most sites, Pit-1 appears to bind as a homodimer with one Pit-1 molecule contacting the high-affinity octamer-related sequence, ATGNATA, and the second molecule binding cooperatively to the 3' located lower affinity A/T-rich region (79, 80, 81). On some sites Pit-1 can bind as a heterodimer with the POU domain factor Oct-1, and on yet other sites it binds as a monomer (82).


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Table 2. Pit-1 DNA-binding sites

 
While Pit-1 also binds to the classical octamer site, it does so with lower affinity than to natural sites, and at least in one experiment seemed incapable of transactivating through octamer sites (79).

2. DNA binding sites for the class II factors Oct-1 and Oct-2. The octamer DNA element, ATGCAAAT, frequently found within gene-regulatory regions, is conserved and functionally important for transcriptional regulation of several genes. These include the B cell-specific immunoglobin genes (83), the ubiquitously expressed small nuclear (sn)RNA genes (84, 85), the cell cycle-specific histone H2B genes (86), and a host of other widely and selectively expressed genes (Table 3Go). Early studies attempting to identify the transcription factors binding to octamer elements led to the isolation of Oct-1 and Oct-2 as the major components of octamer-binding activity in eukaryotic cells. Review of the literature indicates that the Oct-1 POU domain has a strong preference for the core element, ATGCAAAT, but clearly several variants of the core element are compatible with high-affinity DNA binding (Table 3Go). Experiments have also indicated that the bases flanking the core octamer provide additional binding specificity (60).


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Table 3. Oct-1/2 DNA-binding sites

 
Two studies using random DNA-binding selection methods found that Oct-1 can bind to several different DNA sites with high affinity (61, 65), consistent with previously described broad binding specificity for Oct-1 (60). Yet, when the binding sites were aligned, both groups identified an octamer consensus sequence with position 1 (A) and 7 (A) nearly invariant in sites that bear resemblance to octamer sites (65). Both groups found that a "T" in position 1 was common and that a common octamer variant was a "T" instead of an "A" in position 5 (61, 65). Review of the literature describing Oct-1/2 binding sites in gene-regulatory regions of diverse genes also shows a high frequency of octamer-like sequences (Table 3Go). It is striking that alignment of these sites results in a consensus sequence remarkably similar to that identified in the two random site selection studies (Table 3Go). However, this approach is unlikely to give a true representation of the type of sites found in gene-regulatory regions because in their studies, investigators are much more likely to identify and report on the well known octamer site rather than more divergent sites.

Oct-1 can also bind to a distinct site, TAATGARAT (R is a purine), found in the herpes simplex virus immediate early (HSV IE) promoters (87, 88). The affinity of Oct-1 alone for this site is much lower than for that of the octamer element (64), but in contrast to the classical octamer site, this site can promote the formation of a complex of Oct-1 and VP16, which is required for viral transcription (Fig. 2Go). The critical feature of this site is the 3'-GARAT motif, which is necessary for the recruitment of VP16, possibly by a mechanism involving the recognition of specific conformations of Oct-1 (62, 89) or direct nucleotide recognition (90). On this site, the POU-S domain is located on the opposite side of the POU-H domain as compared with Oct-1 bound to a classical octamer site (62).



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Figure 2. Selective protein-protein interactions involving POU domain factors. Interactions of POU domain factors with other proteins are influenced both by the amino acid sequence of the POU domain and the sequence and context of the DNA binding site. a, Pit-1 interacts with GATA transcription factors. On promoters containing binding sites for both Pit-1 and GATA, the interaction seems to be cooperative and results in transcriptional activation (left panel). On promoters containing GATA-binding sites, but lacking Pit-1 binding sites, Pit-1 can inhibit GATA binding to DNA and transactivation. b, The cofactors VP16 and OCA-B interact selectively with Oct-1 and Oct-2. VP16 interacts with Oct-1 on TATGARAT DNA sites, with VP16 contacting the GARAT part of the site. This interaction is stabilized by HCF. Oct-1 and VP16 do not interact on a classical octamer site and VP16 is incapable of interacting with the highly related Oct-2, even on TATGARAT sites, indicating that minor differences in the sequence of the POU domain can direct the specificity of protein-protein interactions. In contrast, OCA-B can interact both with Oct-1 and Oct-2. However, this interaction is restricted to sites related to the classical octamer sequence and does not form on TATGARAT sites.

 
In addition, Oct-1 can bind to the heptamer element CTCATGA found next to the octamer site in immunoglobin heavy chain promoters (91, 92, 93). While divergent from the octamer site, both Oct-1 and Oct-2 can recognize this site, albeit with lower affinity. However, when Oct-1 or Oct-2 occupies the adjacent octamer site, binding to the heptamer site is strongly enhanced (91, 92, 93). Cooperative binding to the heptamer element occurs when the spacing between the two elements is either 2 or 14 bp, suggesting that the coordinated binding is caused by protein-protein interactions (91). This cooperative binding to the heptamer site contributes to transactivation by Oct-1 and Oct-2 (91, 93).

Several divergent sites capable of binding Oct-1 have been identified in diverse genes, including the GnRH gene-regulatory region (28, 29) (Table 3Go). An unusual binding site has been described in the human interleukin 5 (IL-5) promoter. In this site, inverted POU-S binding sites seem to flank two POU-H domain binding sites (94, 95). Yet other sites are similar to the TAATGARAT site in that they only contain recognizable POU-H domain binding sites (Table 3Go). The binding specificity of Oct-1 and Oct-2 has been found to be indistinguishable in several studies, and other studies indicate that the third class II POU factor, Skn-1a, has identical binding preferences (35, 96). These observations suggest that within a POU class, binding preferences tend to be similar.

3. DNA binding sites for class III factors. Studies have shown that the class III POU factor Tst-1 binds to and activates octamer site-dependent promoters (97, 98). Similar to Oct-1, different binding affinities were observed with perfect octamer sites containing distinct flanking sequences, indicating that the flanking sequences are also important determinants of binding affinity for Tst-1 (98). Tst-1 also binds to five distinct sites in the myelin-specific P0 promoter with a consensus sequence, GA(A/T)T(T/A)ANA, which appears unrelated to the octamer site (99). The rat GnRH promoter contains three Tst-1 binding sites that appear to conform to the consensus derived from the Tst-1 binding sites in the P0 promoter (100) (Table 4Go). Tst-1 also binds with high affinity to two sites in the JC virus promoter, but only one of the sites confers transcriptional activation. While they are AT-rich, neither site bears any similarity to octamer sites nor the P0 consensus site (101).


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Table 4. Class III DNA-binding sites

 
Brn-2, like Tst-1, can bind to and activate promoters dependent on octamer sites (102). Rhee et al. (103) employed a random site selection method to determine optimal binding sites for class III POU factors, using Brn-2 as a prototype member. Their study confirmed the ability of class III factors to interact with octamer-like sites, especially those that have an associated heptamer site. In addition, Brn-2 was found to have preference for sites with the consensus ATG(A/C)AT(A/T)0–2ATTNAT, and on these sites, Brn-2 bound as highly cooperative dimers (103). Brn-2 binds to a divergent site in the neuronal promoter of the aromatic L-amino acid decarboxylase gene, a sequence that overlaps with a binding site for winged helix/forkhead protein HNF-3 (104).

Brn-4 DNA binding preferences have also been evaluated by a random site selection method where it was found that the optimal binding site, CAATATGCTAAT, is related to the smaller octamer site, containing a TAAT instead of the AAAT (105). Thus, the optimal binding sites selected with Brn-2 and Brn-4 are different. It is quite possible that these differences are due to methodological variables rather than bona fide binding differences between these two class III POU factors. Since it is likely that all POU domain factors can bind to DNA in different conformations, it is not surprising that different studies have identified distinct binding sites for class III POU factors. Nonoctamer DNA-binding sites for Brn-4 have been found in the striatal D1 dopamine receptor (106) and proglucagon genes (107). These sites seem to be most similar to the Tst-1 sites in the P0 and rGnRH promoters (Table 4Go).

4. DNA binding sites for the class V factor Oct-3. Oct-3 binds with high affinity to octamer sites (108, 109, 110), but also to so called palindromic Oct factor recognition elements (PORE), which simulate a pair of inverted homeodomain sites separated by 5 bp, ATTTG +5 CAAAT, found in the osteopontin enhancer (Table 5Go). In addition to Oct-3, other Oct factors can bind to this site, either as homodimers or heterodimers (111). Oct-3 is reported to transactivate more robustly from this element than a classical octamer site (111).


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Table 5. Oct-3 DNA-binding sites

 
Oct-3 can also bind to and regulate transcription through an element located in the regulatory region of a gene encoding the embryonic stem cell coactivator UTF1. This element, which is one base different from a classical octamer site (Table 5Go), selectively recruits Oct-3 and Sox-2 and is incapable of binding complexes containing Oct-1 and Tst-1 (112).

5. DNA binding sites for the class VI factor Brn-5. In experiments using a random site selection method, Brn-5 was found to prefer the binding site GCATAA(T/A)TTAT, which is related to the class IV factor Brn-3 optimal binding site (103). In different experiments where Brn-5 site selection was performed with a fixed site, GCAT, followed by eight random nucleotides, an octamer-like sequence was selected: GCATATGATAAT (56). However, it is clear that Brn-5 binds poorly to a classical octamer site (56). Alignment of three high-affinity sites suggested a high-affinity consensus site GCATN2–3TAAT (56) (Table 6Go).


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Table 6. Brn-5 DNA-binding sites

 
6. Conclusions. DNA-binding sites capable of binding POU domain factors have been identified with two distinct methods. Studies aimed at determining important gene-regulatory elements have identified several DNA sites that bind POU domain factors important for regulation of the gene in question. Genetic evidence suggests that the Pit-1 binding sites in the GH, PRL, and TSH{beta} genes are bona fide response elements. For most other sites identified in such studies, genetic evidence for their importance is lacking. An alternative approach has been to use a selection of high-affinity binding sites from a set of random sites in vitro. While this approach may identify high-affinity sites, those are not necessarily biologically important sites. However, from these two approaches several general conclusions about POU domain binding sites can be reached.

First, members of the same subclass of POU domain factors tend to have similar DNA-binding preferences, most clearly demonstrated for class II POU factors. Second, while distinct POU classes may have somewhat distinct DNA-binding preferences, a single POU factor can recognize several different DNA-binding sites. Third, POU factors of different classes can often recognize the same element with similar affinity, and all POU factors discovered so far seem to be capable of binding to octamer sites with reasonably high affinity. Fourth, while the core recognition sequence for monomeric binding is often 8 bp long, bases outside the core region may be important for binding affinity and transcriptional activity. Fifth, while POU domain factors can bind as monomers, some factors, such as Pit-1 and class III factors, can homodimerize, especially on appropriate symmetrical sites. Sixth, while transcriptional activation may correlate with binding affinity on monomeric sites, other features of the site, such as the ability to allow dimerization and interaction with other factors, may be important determinants of whether a particular site confers activation (Fig. 2Go). Seventh, the DNA-binding site can determine the ability of a bound POU factor to recruit associated proteins (Fig. 2Go). Finally, target genes that are responsive to POU domain factors frequently have a cluster of POU-binding sites, particularly when the regulatory regions are located at a distance from the promoter.

B. Protein chemistry
The structure of the POU domain has been extensively studied for both Oct-1 and Pit-1, using NMR (113, 114, 115, 116) and crystallographic (66, 117) methods. The similarity in structure between these two POU domains strongly suggests that the basic observations from these studies can be applied to other POU domains. The POU domain is composed of a 74- to 82-amino acid POU-S domain and a 60-amino acid POU-H domain with a 15- to 56-amino acid flexible linker tethering the two domains (Fig. 1Go). The two subdomains are structurally independent, and individually they are capable of low-affinity DNA interactions (64). High-affinity DNA binding, however, requires the intact POU domain, with each subdomain making major groove DNA contacts. The structure of the POU-S domain is characterized by four {alpha}-helices surrounding a hydrophobic core similar to the helix-turn-helix motif of bacteriophage {lambda} and 434 repressor, and 434 Cro DNA-binding domains (113, 115). While somewhat divergent, the POU-H domain, like classic homeodomains, exhibits a helix-turn-helix structure with three {alpha}-helices (118, 119, 120). For both the POU-S and POU-H domains, the second and third helix form a helix-turn-helix structure with the third helix docking to DNA in a major groove where amino acids making direct base contacts tend to be conserved among POU domain factors (121, 122).

The two subdomains do not contact each other, and the linker is not visible in the cocrystals, suggesting that it may be unstructured, perhaps providing flexibility to the POU domain (Fig. 1Go). This flexibility would allow the two subdomains to acquire different orientation and spacing relative to each other, presumably explaining the versatility in DNA sites that can bind POU domain factors, and the variability in surfaces available for interactions with coregulatory proteins (63). This flexibility may depend, in part, on the length of the linker as evidenced by results showing that the Brn-2 POU domain can adopt two different orientations on DNA, while this was not observed with Brn-3, which contains a shorter linker (62, 63). An effect of the linker on DNA binding specificity was also found in experiments comparing binding of chimeric molecules from the Oct-1 and Pit-1 POU domains (123). It has been shown that optimal binding of Oct-1 to an octamer site requires a minimum linker length between 10 and 14 amino acids (67). Oct-1 molecules with a shorter linker bind DNA only if the POU-S recognition site is inverted in orientation, apparently bringing it closer to the POU-H domain. In addition, mutations of some conserved residues in the Oct-1 linker altered DNA binding, indicating that there are both sequence and length requirements for the function of the linker (67).

An example of the subdomain flexibility is provided by the binding of Oct-1 to the octamer element (ATGCAAAT) where the POU-S domain recognizes the 5'-ATGC-part and the POU-H domain recognizes the 3'-AAAT-part. On the TAATGARAT site from the herpes simplex virus (HSV) IE promoter, the Oct-1 POU-H domain recognizes the 5'-TAAT part, and the POU-S domain recognizes the 3'-GARAT part in a flipped orientation as compared with Oct-1 binding to an octamer site (62).

While the primary, secondary, and tertiary structures are similar, crystallographic studies of Oct-1 and Pit-1 on two different DNA sites have shown quite distinct structures as to the relationship between the two POU subdomains (66, 117) (Fig. 1Go). The Oct-1 POU domain binds to opposite faces of an octamer DNA-binding site (the histone H2B promoter octamer). In contrast, the Pit-1 subdomains bind to perpendicular faces of a palindromic DNA site (derived from the PRL 1P site), with the POU-S domain exhibiting flipped orientation compared with Oct-1 structure (Fig. 1Go). In addition, while Oct-1 binds as a monomer to an octamer site, Pit-1 forms homodimers on the palindromic PRL 1P-related site via interactions between the C terminus of the DNA-recognition helix of the homeodomain and helix {alpha}1 and the loop between helices {alpha}3 and {alpha}4 of the POU-S domain. Most likely, these differences in structure between Oct-1 and Pit-1 are due to the different DNA-binding sites used for cocrystallization, which is supported by data indicating that the Pit-1 POU domain binds as a monomer to a classical octamer site (124).

It has been shown that POU factors can be modified by phosphorylation. Oct-1 and Pit-1, for example, are phosphorylated on homologous residues in the POU domain, Ser-385 and Thr-220, respectively, and this phosphorylation leads to decreased DNA binding to octamer and GH POU sites (125, 126). On other sites, such as those found in the TSH{beta} and PRL promoters, phosphorylation by protein kinase A or C enhances DNA binding (127, 128). While cAMP-dependent kinase can phosphorylate these sites in vitro, the identities of the relevant kinases operating in vivo are unclear. For Oct-1, this phosphorylation occurs in a cell cycle-specific manner, thus explaining the S phase-specific activation of the histone H2B gene by Oct-1 (86, 125). Jun kinase (JNK)/stress- activated protein kinase can bind to the activation domain of Brn-5 and phosphorylate its POU domain on sites that are distinct from the aforementioned Oct-1/Pit-1 phosphorylation sites. This phosphorylation leads to increased binding to DNA and enhanced transactivation (129). Finally, it has been demonstrated that Pit-1 can be acetylated by CREB-binding protein (CBP), but the biological significance of this finding remains to be determined (130).

C. Protein-protein interactions
POU domain factors regulate transcription by interacting with other proteins. POU interacting proteins can be classified into four classes: DNA-binding transcriptional activators, coregulators, basal factors, and replication factors (131). A prominent feature of POU factors is their ability to form cooperative homodimers, and even heterodimers with other POU factors, especially when bound to the appropriate DNA site (80, 82, 132) (Fig. 2Go). POU factors also have a striking ability to interact with a variety of divergent structural domains in heterologous factors, including other DNA-binding proteins and coregulators that are incapable of independent DNA binding. In this chapter we will review protein-protein interactions involving those POU factors expressed in the neuroendocrine system (Table 7Go). Many of these interactions may not be directly relevant to regulation of gene expression in the hypothalamo-pituitary axis, but the principles derived from these studies are likely to apply to studies of POU domain factors in the neuroendocrine system (Fig. 2Go).


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Table 7. Protein-protein interactions involving POU domain factors

 
1. Pit-1 interactions.
a. Interactions with DNA-binding proteins.
Pit-1 forms highly cooperative homodimers on the natural binding sites in regulatory regions of the GH, PRL, and TSH{beta} genes (80). This Pit-1 homodimerization has been shown in living cells with fluorescence resonance energy transfer microscopy (FRET) (133). Functional experiments indicate that the POU-S domain is important for Pit-1-Pit-1 interactions and that homodimerization is important for efficient transactivation (80). The ability of some natural Pit-1 mutants to inhibit Pit-1 action in a dominant negative fashion further supports the importance of Pit-1 homodimerization in gene activation (see Pit-1 mutations as a cause of combined pituitary hormone deficiency in humans). In addition, Pit-1 can form heterodimers with Oct-1, which results in synergistic transactivation of the PRL promoter (82).

Pit-1 can also interact to varying degree with several heterologous DNA-binding proteins which, when bound to the same promoter, often lead to synergistic transactivation. These interacting factors include the nuclear hormone receptors TR (thyroid hormone receptor), RAR (retinoic acid receptor), RXR (retinoid X receptor), ER (estrogen receptor), VDR (vitamin D receptor), and GR (glucocorticoid receptor). Pit-1, for example, interacts strongly with RXR and more weakly with TR and RAR, which may play a role in synergistic regulation of the GH promoter (134, 135, 136). Pit-1 can also interact with ER (137, 138, 139, 140) and VDR (141) in synergistic activation of the PRL gene. The human PRL promoter is inhibited by glucocorticoids, mediated by a gene regulatory region containing Pit-1 binding sites but no glucocorticoid response element (GRE). Studies show that GR and Pit-1 can interact in solution and that the inhibition does not require GR to bind to DNA (142).

Pitx1, a bicoid-like homeodomain factor, interacts with the N terminus of Pit-1 (143) and synergistically transactivates the PRL promoter with Pit-1 (144, 145). A direct interaction of Pit-1 with the related Pitx2 removes an inhibitory effect of a 39-amino acid C-terminal sequence of Pitx2, thus promoting DNA binding and transactivation (146). Pit-1 also interacts in solution with the LIM homeodomain protein P-Lim (Lhx3) and acts synergistically with P-Lim to regulate the PRL enhancer/promoter (147).

Synergistic interactions between Ets-1 and Pit-1 may be important in regulation of the PRL promoter. The synergistic gene activation requires direct Pit-1-Ets-1 protein-protein interaction and is not observed with Ets-2 (148). This interaction, which has been shown in living cells with FRET microscopy (133), maps to the POU domain (149). Pit-1{beta}, an isoform of Pit-1 containing 26 additional amino acids in the N terminus, is incapable of transcriptional synergism with Ets-1, apparently because of additional interaction surface that maps to the N-terminal sequence specific to this isoform (149).

Interactions between Pit-1 and the transcription factor GATA-2 are more complex and have distinct features depending on whether both factors bind to DNA (150, 151) (Fig. 2AGo). Pit-1 and GATA-2 can interact in solution (150, 151), and the interaction interface maps to the POU-H domain of Pit-1, specifically the N-terminal basic residues and the surface of the second helix (P26, Q29) (151). In GATA2, the C-terminal DNA-binding zinc finger and an adjacent cluster of basic residues seem to be important. Pit-1 can inhibit binding of GATA-2 to cognate DNA sites on promoters that do not have Pit-1 binding sites, such as the gonadotrope-specific SF-1 promoter (151) (Fig. 2AGo). This seems to be important for generation of the gonadotrope phenotype. In contrast, Pit-1 leads to synergistic activation with GATA-2 on promoters containing adjacent Pit-1 and GATA-2 sites, such as the thyrotrope-specific TSH{beta} promoter (150, 151) (Fig. 2AGo). As described later, these interactions may be important for the formation of both thyrotrope and gonadotrope cell types.

b. Interactions with coregulator proteins.
In addition, Pit-1 has been demonstrated to interact with coregulators. The POU domain of Pit-1 interacts with CREB binding protein (CBP) through two cysteine-histidine rich domains (C/H1 and C/H3) (152, 153) (Fig. 3Go). Pit-1 can also, via its POU-H domain, interact with the corepressor N-CoR (nuclear receptor and corepressor) (153). As will be described later, these interactions may be important for transactivation and the role of Pit-1 in signal transduction.



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Figure 3. A schematic model describing mechanisms of transcriptional regulation by Pit-1. Pit-1, which binds as a dimer to DNA, can associate with the CREB-binding protein (CBP)/p300 complex mediating histone acetylation and gene activation. CBP may also mediate cAMP responses on Pit-1 target genes. Alternatively, Pit-1 may associate with complexes that mediate histone deacetylation and repression of gene expression. Presumably, differential association with these two complexes can determine the transcriptional outcome of Pit-1 binding to a promoter region. In addition, the N terminus of Pit-1 participates in transcriptional activation, perhaps by making direct contacts with the core transcriptional machinery. In addition, several factors, such as the DNA site proteins bound to adjacent DNA sites and modifications of Pit-1 itself, contribute to transcriptional regulation.

 
2. Oct-1 and Oct-2 interactions.
a. Interactions with DNA-binding proteins.
The Oct-1 POU domain forms transient homodimers in solution in vitro, requiring both the POU-S and the POU-H domains (132). This interaction, which is relatively weak, is stabilized by binding to the octamer-heptamer site, consistent with other experiments showing that this site mediates cooperative binding (132). Oct-1 can also heterodimerize with other POU factors, including Pit-1 (82), Oct-3 (154), Oct-2, and Tst-1 (132).

Both Oct-1 and Oct-2 have been shown to interact with DNA-binding factors from other classes, including nuclear hormone receptors, such as RXR (138). The interaction interfaces seem to involve the Oct-1 POU-H domain, but not the POU-S domain, and the DNA-binding domain and hinge region of RXR. Functional studies suggest that Oct-1 may negatively regulate nuclear signaling pathways by altering the DNA-binding ability of nuclear receptor-RXR heterodimers. In contrast, on artificial promoters containing vitamin D response elements and octamer sites, Oct-1 and the vitamin D receptor exhibit cooperative binding and transcriptional synergism mediated by the DNA-binding domain of the vitamin D receptor (155).

In solution, the POU domains of Oct-1 and Oct-2 can bind to the DNA-binding domain of GR, including an interface that contains amino acids C500 and L501 (156). Again the POU-H domain of Oct-1 seems to be responsible for the interaction (156). Microinjection experiments in zebrafish embryos suggest that such DNA-independent effects of GR involving interactions with the Oct-1 and Oct-2 POU-H domains are biologically important (157). The GR-Oct-1 interaction can both modulate the transcriptional activity of Oct-1 on certain promoters, like the GnRH promoter as detailed later (158), and the activity of GR on its target genes (138). On the mouse mammary tumor virus (MMTV) promoter, it has been shown that Oct-1 and GR bind in a cooperative fashion and that this leads to a synergistic transcriptional regulation on naked DNA templates in vitro (159). Oct-2 can also bind cooperatively with GR, and this also results in synergistic transcriptional regulation (156, 160). In vivo results indicate that Oct-1 binding to the MMTV promoter is strictly glucocorticoid dependent, consistent with a role for GR in remodeling of chromatin to promote access of other factors to the MMTV promoter, such as nuclear factor 1 (NF-1) and Oct-1 (161, 162).

On templates containing GREs and octamer sites, Oct-2A and GR can synergize transcriptionally (156, 163). However, when GR sites are not present, GR strongly inhibits transactivation by Oct-2A, while the reciprocal is not true. This effect does not seem to depend on interference with Oct-2A DNA binding, but more likely is due to competition for rate-limiting coactivator molecules (163). A minimal promoter driven by Oct-1, binding to an octamer element, can also be inhibited by GR in a hormone-dependent manner. This interaction seems to be mediated by a strong solution interaction between GR and Oct-1, resulting in inhibition of Oct-1 DNA-binding (164). This interaction, which seems to involve the POU-H domain of Oct-1, can be inhibited by GR binding to a GRE (156). While the mechanism is unclear, functional analyses indicate that androgen-mediated repression of the dehydroepiandrosterone sulfotransferase gene promoter requires Oct-1 binding to the promoter. Since there seems to be no direct AR binding to this promoter, AR-Oct-1 interactions may be important (165).

Oct-1 can interact with several other DNA-binding factors, including Sp1 (166, 167), AP-1 (168, 169, 170), CCAAT/enhancer binding protein-{beta} (C/EBP{beta}) (171), NF-1 (172, 173), and MEF2 (174). Oct-1/2 interactions with heterologous DNA-binding proteins can either result in transcriptional synergism, as exemplified by the AP-1/Oct-1 interaction (168, 169, 170), or interference as exemplified by C/EBP{beta} inhibition of Oct-1 function (171).

Interaction of the high mobility group protein HMG2 with the POU domains of Oct-1 and Oct-2 leads to cooperative binding (175). The related HMG I(Y), a known octamer-binding protein, functions as a coactivator with Oct-2A but not Oct-1 for HLA-DRA transcription. Apparently HMG I(Y) facilitates the binding of both Oct-1 and Oct-2 to octamer sites (176) by a mechanism that involves interactions between HMG I(Y) and the POU domains of Oct-2 and Oct-1. However, synergistic transactivation of the HLA-DT gene is only found with Oct-2 and seems to depend on sequences within the C terminus of Oct-2 (177).

b. Interactions with coregulator proteins.
The B cell-specific coactivator OCA-B (also referred to as OBF-1 and Bob-1), a 256-amino acid, proline-rich protein with no close homologs in the database, interacts specifically with the POU domains of Oct-1 and Oct-2 and is required for B cell-specific activation of immunoglobin genes (178, 179, 180, 181, 182, 183). By interacting with Oct-1 and Oct-2, OCA-B can be recruited to a subset of octamer sites where it serves a coactivator function for transcription (184) (Fig. 2BGo). In part, a strong transactivation domain in the C terminus of OCA-B mediates this effect, while the N terminus contains the domain interacting with POU domains (185). This interaction is specific for Oct-1 and Oct-2 (Fig. 2BGo) and not observed for other POU domain factors such as Oct-3, Oct-6, and Pit-1. The specificity of the interaction of OCA-B with both the POU-S and the POU-H domains is determined by residues in the first helix of the POU-S domain (L6 and E7) and the end of the third POU-H domain helix (K155 and I159) (124, 184). Other residues in the POU domain, including L53 and N59 in the POU-S domain, have been shown to be important for the Oct-OCA-B interactions. However, these residues are conserved in POU domain factors that do not interact with OCA-B and are thus unlikely to determine the specificity of the interaction.

Immunoglobin promoters are strongly activated by OCA-B, whereas the histone H2B promoter is poorly activated, suggesting that there is some promoter-specific restriction of the ability of OCA-B to transactivate. Further specificity is observed on the immunoglobin promoters because OCA-B only seems to activate on sites in the proximal promoter but not on distally located enhancer sites (124). In addition, the Oct-1/Oct-2-OCA-B complex can only occur on octamer sites that contain an A in the fifth position of the octamer site, such as found in the classical octamer site (Fig. 2BGo). Position +3, +4, and +6 also appear to be important (124, 184). Apparently, OCA-B makes direct contacts with the DNA backbone in the middle of the octamer site, via its N terminus, in addition to POU domain contacts (186, 187). It has been proposed that OCA-B clamps the two POU subdomains together and at the same time bridges the DNA within the octamer motif at several positions. According to this model, OCA-B may help organize the conformation and stabilize the DNA binding of the Oct POU domain on DNA (124, 184). There is also evidence that binding of OCA-B to the Oct-1 POU domain/octamer complex induces a partial folding of OCA-B (186).

Another extensively studied coregulator is VP16. In human cells infected with the herpes simplex virus (HSV), viral gene expression is initiated with the viral protein VP16, which regulates the HSV immediate-early (IE) genes. VP16 does not bind DNA directly, but is instead recruited to IE promoters by its association with Oct-1 (87, 188, 189, 190, 191, 192) (Fig. 2BGo). Another cellular protein, host cell factor (HCF), is required for nuclear import of VP16 (193) and stabilization of the VP16-Oct-1 interaction (194, 195, 196, 197). After infection, VP16 first forms a complex with HCF, which then promotes its interaction with Oct-1 and binding to the TAATGARAT motif in the HSV IE promoters (Fig. 2BGo). The interaction of the Oct-1 POU domain and VP16 is selective and not observed with the highly homologous Oct-2 POU domain (198) (Fig. 2BGo). Selective residues, particularly a glutamic acid residue (E22) located on the surface of the second helix of the POU-H domain, are critical for the recognition by VP16 (199, 200). In the Oct-2 POU-H domain, the analogous residue is an alanine, thus precluding interaction with VP16. In addition, the interaction between Oct-1 and VP16 requires the 3'-end GARAT of the TAATGARAT motif to be intact for ternary complex formation (89, 90) (Fig. 2BGo). VP16 alters gene regulation by Oct-1 in two distinct ways. First, it provides a transactivation domain that is highly active on mRNA promoters where the Oct-1 transactivation domain is inactive, and second, it stabilizes the Oct-1-binding to VP16-responsive elements (184).

c. Interactions with basal transcription factors.
SNAPc (snRNA activating protein complex; also referred to as PTF) is a basal transcription factor, composed of several well defined peptides, that binds to promoter elements called the proximal sequence element (PSEs) in both RNA Pol II and Pol III snRNA promoters (84, 201, 202). Oct-1 binds to the enhancer or distal sequence elements (DSEs) in snRNA promoters, which leads to cooperative binding with SNAPc via a protein-protein interaction involving the POU-S domain of Oct-1, especially residue E7, and the C-terminal region of SNAP190, a major component of the SNAPc (203). The result is an enhanced transcriptional activation by Oct-1-mediated recruitment of SNAPc to the PSE of snRNA genes (204). The carboxy terminus of SNAP190 acts as an inhibitor of SNAPc DNA binding, but the interaction with the Oct-1 POU domain relieves the inhibition and promotes cooperative binding; SNAPc binds with 8- to 10-fold higher affinity when Oct-1 is bound to the DSE (205, 206).

The POU domains of Oct-1 and Oct-2 have been shown to interact with the TATA binding protein TBP (207). Since this interaction was in solution and not on DNA, its significance is somewhat unclear. However, this finding is consistent with the observation that Oct-1 and Oct-2 can facilitate preinitiation complex formation (208). In addition, the binding of Oct-1 and Oct-2 to the lipoprotein lipase promoter octamer site was shown to be stimulated by transcription factor II B (TFIIB), apparently via protein-protein interactions (209).

A yeast two-hybrid screen with the Oct-1 POU domain identified MAT1 as a POU domain-binding protein capable of binding to Oct-1, Oct-2, and Oct-3 POU domains. MAT1 is required for the assembly of cyclin-dependent kinase (CDK)-activating kinase (CAK), which is functionally associated with the general transcription factor IIH (TFIIH). The interaction between POU domains and MAT1 can target CAK to octamer binding factors and promote their phosphorylation. This interaction may play a role in the recruitment of TFIIH to the preinitiation complex (210).

d. Interactions with replication factors.
Oct-1 is involved in adenovirus replication where it binds to the highly conserved core origin and interacts via its POU domain with one of the three viral proteins required for replication, the precursor terminal protein (pTP) (122, 211, 212). The interaction seems to involve several regions of the pTP protein (213). The POU-H domain binds to the pTP-DNA polymerase complex (213), but more weakly than the intact POU domain. No binding is observed with the POU-S domain alone (214). Presumably, this interaction facilitates the recruitment of the pTP-DNA polymerase complex to the origin of replication. The stimulation of adenovirus DNA replication seems to depend on a property of the POU domain that is common to many POU domains because other POU domain factors, including Pit-1 and Tst-1, can also stimulate DNA replication (215).

3. Class III POU interactions.
a. Interactions with DNA-binding proteins.
Based on far-Western and mammalian two-hybrid experiments, all class III POU domain factors can interact with each other via the POU homeodomain (216). Consistent with this observation, Brn-2 exhibits highly cooperative homodimerization on a consensus nonoctamer binding site (103).

Sox/HMG proteins are transcription factors that contain Sry boxes that mediate binding to the minor groove of DNA. Such factors may frequently interact with POU domain factors that bind to the major groove of DNA. Tst-1 (Oct-6) can interact with HMG I(Y) in solution, which facilitates Tst-1-binding to an AT-rich site in the JC viral regulatory region (217). Tst-1 can also interact with the related HMG2 (218). Both Tst-1 and Brn-1 can cooperate with different Sox proteins in transcriptional activation. Specifically, Brn-1 can synergize with Sox-11 when both proteins are bound to adjacent elements; the synergism depends on the transactivation domains in both proteins. Such POU-Sox interactions may be important for a combinatorial code required for cell-specific transcriptional activation (219, 220).

b. Interactions with coregulator proteins.
Tst-1 can interact with the large T antigen from the human papovavirus JC virus, and this interaction seems to lead to transcriptional activation on the early and late promoters from the JC virus (101, 221, 222). The amino-terminal 82 residues of the large T antigen and the POU domain of Tst-1 mediate this interaction, but for a functional effect on transcription, the N-terminal transactivation of Tst-1 is also required. This functional effect is specific for Tst-1, because while Brn-1 is also capable of interacting with large T antigen, this interaction is not transcriptionally productive, apparently because of differences in the transactivation domains of Brn-1 and Tst-1 (223).

4. Oct-3 interactions.
a. Interactions with DNA-binding proteins.
Oct-3 can interact with the HMG-box protein Sox2 (224), and these two factors have been implicated in synergistic regulation of the fibroblast growth factor 4 (FGF-4) gene (49) and the embryonic stem cell coactivator gene UTF-1 (112). The synergism between Oct-3 and Sox2 on the FGF-4 promoter seems to be due to cooperative binding, which can be disrupted by increasing the distance between the two binding sites (109). In contrast, Sox2 functionally antagonizes Oct-3 on the ostepontin gene-regulatory region where its binding site is adjacent to that of Oct-3 (111). Oct-3 and Sox2 interact directly in solution, with the interaction interface being the POU domain and the Sox2 HMG domain (109).

b. Interactions with co-regulator proteins.
In embryonic stem cells Oct-3 transactivation is independent of the distance of the octamer site from the promoter, but in differentiated cells, Oct-3 transactivation from a distance seems to require stem cell-specific coactivators that bridge the remotely bound Oct-3 to the basal transcriptional machinery (225). While these factors remain to be identified, it is known that transactivation by Oct-3 is strongly stimulated by E1A in 293 and HeLa cells and depends on both the intact POU domain and the transactivation domain of Oct-3. This effect is specific because it is not found with Oct-1 and minimally with Oct-2. Direct binding of Oct-3 to E1A was also demonstrated (225). The Oct-3 POU domain can associate with two distinct domains on the E1A protein, CR1 and CR2, and it can also associate with the HPV E7 protein (226). These data suggest that viral oncoproteins have characteristics that mimic a stem cell-specific activity (226).

5. Conclusions.
From studies on the protein-protein interaction characteristics of POU domain factors several general conclusions can be drawn. First, most factors that interact with POU domain proteins have been found to interact with the POU domain rather than other parts of the proteins. This finding may be due, in part, to technical difficulties in identifying factors that interact with the transactivation domains outside the POU domain. However, these results indicate that the POU domain is not only a DNA-binding domain but also an important interface for regulatory proteins. Second, POU domain factors seem fairly promiscuous as to their ability to interact and synergize with diverse DNA-binding proteins bound to the same promoter. Most POU domain factors have been shown to interact in such a way with nuclear hormone receptors and HMG proteins. Third, while the POU domain is highly conserved, most POU domain interactions with coregulators are remarkably selective; apparently proteins are able to discern small differences in POU domain sequence (Fig. 2BGo). Thus, the E1A protein interacts strongly with Oct-3 but not Oct-1 or Oct-2. VP16 interacts strongly with Oct-1 but not Oct-2, Oct-3, or Tst-1 (Fig. 2BGo). OCA-B interacts selectively with Oct-1 and Oct-2, but not with Oct-3 or Tst-1 (Fig. 2BGo). This selectivity for protein-protein interactions by POU domains is in stark contrast to the lack of selectivity in DNA-binding preferences. Fourth, the association of a coactivator with a POU domain factor may be stabilized by a simultaneous direct interaction of the coactivator with DNA, such as that found with Oct-1/2 and OCA-B (Fig. 2BGo). Fifth, some POU factor-coactivator complexes can only form on selective DNA sites, perhaps in part due to direct DNA contacts of coactivators or due to DNA-induced conformational changes of the POU domain as has been described with OCA-B/Oct-1 and VP16/Oct-1 interactions (Fig. 2BGo). For example, the Oct-1/2-OCA-B interaction requires an "A" in position 5 of an octamer site (ATGCAAAT) (184), and the Oct-1-VP16 interaction requires the GARAT part of a TAATGARAT site for ternary complex formation (90). Sixth, additional functional specificity is provided by sequences outside the POU domain, such that two distinct POU domain factors may be capable of physical interaction with a coregulator, but only one of the interactions will result in transcriptional activation, apparently because of specific sequences in the transactivation domain. Finally, while some protein-protein interactions involve only one of the subdomains of the POU domain, e.g., the interactions of VP16 with the POU-H domain and SNAPc with the POU-S domain, others such as OCA-B interact simultaneously with the POU-S and the POU-H domains.

D. Mechanisms of transactivation
1. Transactivation domains.
While the N- and C-terminal domains in POU domain factors are thought to act as transactivation domains, little is known about their structures. These domains, which frequently contain polymeric amino acid stretches, are poorly conserved between different POU domain factors, consistent with the idea that they confer specificity to the action of different factors, often binding to the same DNA element. The N terminus is serine/threonine rich in Pit-1, alanine/glycine rich in Tst-1, proline rich in Oct-3, and glutamine rich in Brn-2. The N- and C-terminal transactivation domains of Oct-2 have been most extensively characterized (227, 228, 229, 230). The N terminus contains an 18-amino acid glutamine-rich motif, and the C terminus contains a proline-rich domain (231). The function of these motifs is enhanced when they are combined or reiterated independently (229, 232), suggesting that they have a modular structure. The Oct-1 transactivation domain appears to be fairly specific for snRNA promoters and has less effect on mRNA transcription, in contrast to the Oct-2 transactivation domains that are active on mRNA promoters (184, 228).

Studies on Oct-3 suggest that transactivation domains may work in a cell-specific manner (233). The N-terminal sequence of Oct-3 fused to the GAL4 DNA-binding domain can transactivate in all cell types tested, whereas the C-terminal sequence shows cell-type specificity in the same assay. This cell type specificity of the C-terminal domain seems to be imposed by the Oct-3 POU domain because it functioned in all cell types tested when the C terminus was fused to Pit-1 POU domain. It is further possible that the transactivation specificity is regulated by phosphorylation as the variation in transactivating ability of the C-terminal domain correlates with differences in the phosphorylation status of Oct-3.

Studies on Pit-1 have defined additional specificity conferred by the N-terminal transactivation domain (234). Thus, synergistic activation by Pit-1 and the estrogen receptor on a PRL reporter construct requires an N-terminal 25-amino acid domain of Pit-1 that is not required for analogous synergism on the GH promoter. This synergy, which depends on two of three tyrosine residues, spaced by six amino acids, is preferentially used on sites where Pit-1 binds as a monomer instead of a dimer. These data suggest that the DNA-binding site, dictating whether Pit-1 binds in dimeric or monomeric form, can alter the segment of the N terminus used as a synergy domain.

The N terminus of Brn-2 contains a glutamine-rich region that is mainly encoded by CAG residues (36). Similar nucleotide triplets that can be expanded are found in disease genes causing fragile-X syndrome and myotonic dystrophy (235). It is unknown whether the same mutational mechanism might involve the Brn-2 gene. A polyglutamine tract-binding protein, PQBP-1, capable of binding to the polyglutamine tract of Brn-2 and other such tracts of triplet repeat disease, has been identified (236). While the function of this novel protein is unknown, it is known to be localized in the nucleus and capable of interfering with transactivation by Brn-2.

The N-terminal sequences of POU factors can also mediate repression, including regions from the N terminus of Oct-2 (237, 238, 239, 240, 241, 242). Oct-3 binds to the promoter of Rex-1, which encodes an acidic zinc finger protein expressed at high levels in embryonic stem cells (108). Depending on the cellular environment, Oct-3 can either activate or repress the promoter, with distinct domains within the N terminus being responsible for repression and activation.

2. Transactivation and chromatin.
Gene expression is influenced by chromatin structure (243). Histones are regulated by acetylation of lysines in their N-terminal tails, allowing changes in histone conformation generally associated with increased access of DNA-binding proteins to promoters. In contrast, histone deacetylation is coupled to transcriptionally silent chromosomal domains. Many transcriptional coactivators possess intrinsic histone acetylation activity that is targeted to specific genes through interactions with DNA-binding proteins. Repressors, on the other hand, can recruit deacetylating enzymes to promoters, either directly or via the corepressor mSin3 (244, 245).

N-CoR, originally identified as a nuclear receptor corepressor (246), has been reported to bind to the homeodomain of Pit-1 and actively suppresses transactivation by Pit-1. This suppression is dependent on mSin3, SAP30, and histone deacetylase (153, 247). N-CoR may be limiting under certain conditions, and its binding to other transcription factors, such as nuclear hormone receptors, may indirectly activate transcription by Pit-1. The Pit-1 POU domain also associates with the coactivator complex consisting of CBP/p300 and P/CAF, both of which possess histone acetylase activity (152, 153) (Fig. 3Go). Thus, the transcriptional activity of Pit-1 may be mediated by the competing binding of complexes responsible for either acetylation or deacetylation, resulting in activation or repression (Fig. 3Go).

3. Conclusion.
Ultimately, it is likely that POU domain factors mediate their transcriptional activation by a combinatorial mechanism involving the N- and C-terminally located transactivation domains and coactivators/corepressors that interact with the POU domain (Fig. 3Go). Since the involved coregulators participate in gene activation by many different transactivators, it is likely that the unique transactivation domains of POU domain factors provide specificity to the activation (228).


    III. Development of the Hypothalamo- Pituitary Region
 Top
 Abstract
 I. Introduction
 II. Structure and...
 III. Development of the...
 IV. Expression and Function...
 V. Relevance of POU...
 References
 
The mature pituitary gland is composed of three distinct anatomical and functional entities (Fig. 4Go) (139, 248, 249, 250): 1) the anterior lobe with five major hormone-producing cell types that respond to neuropeptides released from hypothalamic nuclei carried to the anterior pituitary gland via the portal circulatory system; 2) the posterior lobe containing specialized astroglia referred to as pituicytes, and magnocellular neuronal axons projecting from hypothalamic nuclei, releasing vasopressin and oxytocin (OT); and 3) the intermediate lobe containing melanotropes and endorphin- secreting cells (Fig. 4Go).



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Figure 4. A schematic representation of the adult pituitary gland. The three lobes of the pituitary gland, anterior, intermediate, and posterior, are indicated with the main hormone-producing cell types. The X label over somatotropes, lactotropes, and thyrotropes indicates that these cells do not develop in Pit-1-mutated individuals.

 
The hypothalamus and the anterior pituitary gland develop from distinct regions of the most anterior part of ectoderm primordia (251). Yet the development of these two organs is highly coordinated with neuronal projection arriving in the median eminence and the posterior pituitary gland at about the same time as these neurons start producing neuropeptides and receptors for these peptides become expressed in the anterior pituitary gland. Classical embryological experiments have suggested that the development of the anterior pituitary gland is dependent on inductive signals from the diencephalon (252, 253, 254, 255).

Most of the hypothalamus appears to arise from the neuroepithelium ventral to the hypothalamic sulcus while the preoptic region arises rostral to the optic sulcus (256). During development of the hypothalamus, between embryonic days 11 and 18 (e11 and e18) in the rat, periventricular neurosecretory cells become organized into several nuclei. These include the paraventricular (PVH), supraoptic (SO), arcuate, and periventricular nuclei (PVN). Development of the hypothalamus appears to progress in an outside-in gradient with the late-arising neurosecretory cell types occupying the most medial or periventricular zone of the hypothalamus. For descriptive purposes, four rostrocaudal levels of the hypothalamus can be described: preoptic, anterior, tuberal, and mammillary.

Within the hypothalamus, two distinct neurosecretory systems are organized (Fig. 5Go) (256). One system is composed of magnocellular neurons that project axons directly into the posterior lobe of the pituitary gland (Fig. 5Go). The magnocellular neuronal system includes neurons of the PVH and SON that synthesize OT and vasopressin (VP) and release these peptides into the posterior lobe of the pituitary gland. The second system is composed of parvocellular neurons that synthesize neuropeptides released into the pituitary portal circulation for regulation of the anterior pituitary gland (Fig. 5Go). In addition to the magnocellular neurons, the PVH also harbors parvocellular neurons that synthesize, among other neuropeptides, CRH and TRH for regulating the ACTH/adrenal axis and the TSH/thyroid axis, respectively. In the anterior periventricular and arcuate nuclei are parvocellular neurons that provide dopaminergic control of lactotrophs, and somatostatin/GRH control of somatotrophs. GnRH neurons originate in the olfactory placode and migrate during embryonic development to the hypothalamus (257). GnRH is synthesized in scattered neurons throughout the hypothalamus, especially in preoptic hypothalamic neurons. It is involved in the initiation of puberty and regulation of FSH and LH synthesis in the anterior pituitary gland and thereby regulates reproduction.



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Figure 5. A schematic representation of the adult hypothalamo-pituitary axes. Two types of neurons convey signals from the hypothalamus to the pituitary gland. Magnocellular neurons located in the SON and PVN project their axons directly into the posterior lobe of the pituitary gland where they release vasopressin (AVP) and OT. In contrast, parvocelluar neurons, located in several nuclei, including the paraventricular and arcuate nuclei, project their axons to the median eminence. There, these neurons release pituitary regulating signal substances that are carried via the pituitary portal circulation into the anterior lobe of the pituitary gland. The crossed out neurons are those missing in Brn-2-mutated mice.

 
The anterior pituitary gland originates from an invagination in the oral ectoderm, referred to as Rathke’s pouch (Fig. 6Go). When this oral ectoderm makes contact with the overlying neuroectoderm, around e9 in the mouse, a cascade of signaling events is initiated that ultimately lead to the generation of the anterior and intermediate lobes of the pituitary gland containing six distinct hormone-producing cells by e17.5 (139, 258). These cell types are corticotropes secreting ACTH, melanotropes secreting MSH, gonadotropes secreting LH and FSH, thyrotropes secreting TSH, somatotropes secreting GH, and lactotropes secreting PRL.



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Figure 6. A model describing pituitary gland development in the mouse. At e6.5 a part of the anterior ectoderm is already specified to form the hypothalamus and pituitary gland (not shown). At e10 the rudimentary Rathke’s pouch is marked by expression of the LIM homedomain factor, Plim (Lhx3), within a larger region of Pitx-1-expressing cells in the oral ectoderm. Presumably, these transcription factors are responding to signals, including Shh, which is excluded from Rathke’s pouch, and Wnt5a, BMP-4, and FGF-8 released from the diencephalon. Later, around e11, these signals set up a spatial pattern of transcription factor expression as indicated. As development proceeds, the appearance of hormone-expressing cells appears in a temporal- and spatial-specific manner that corresponds to the pattern of transcription factor expression. The first hormone-producing cells to appear, around e12, are the Pit-1-independent rostral tip thyrotropes (Tr) and corticotropes (C). Later, around e15, gonadotropes (G) and caudomedial thyrotropes (T) appear in a ventral location, and somatotropes (S) and lactotropes (L) appear more dorsally in a caudomedial location. At that stage, corticotropes are widely distributed in the anterior pituitary gland. Somatotropes, lactotropes, and caudomedial thyrotropes form in a location that corresponds to the expression domain of Pit-1. For illustrative purposes the patterns of hormone-producing cells are shown as strictly demarcated segments, but in reality there are no strict boundaries in the developing gland. Later, in the adult anterior pituitary gland, hormone-producing cells are intermixed.

 
These cell types form in a spatial-specific manner earlier in mouse pituitary ontogenesis, around e10.5–14.5, during a period of active cell proliferation (Fig. 6Go). Thyrotropes and gonadotropes are most ventral and somatotropes and lactotropes reside in a dorsal position (139, 258) (Fig. 6Go). During this stage of pituitary organogenesis, at e15, corticotropes are distributed throughout the anterior pituitary gland (258, 259, 260). The spatial restricted organization of thyrotropes, gonadotropes, somatotropes, and lactotropes may be regulated by gradients of signaling molecules, including sonic hedgehog, bone morphogenic proteins (BMPs), FGFs, and Wnts, which in turn create overlapping spatial gradients of transcription factors (Fig. 6Go). Thus, the transcription factors Nkx3.1, Six3, and Prop1 are expressed predominantly dorsally; Isl1, Brn-4, P-Frk, SF-1, and GATA-2 are expressed predominantly ventrally; and Pit-1 is expressed in an intermediary location, the site where lactotropes and somatotropes initially appear (248, 249).

BMP4 signaling from the ventral diencephalon seems to be important for the early formation of the Rathke’s pouch and seems to be linked to the induction of the transcription factor Isl1 (261). Later, FGF8 released from the ventral diencephalon and BMP2 released from mesenchymal cells ventral to the pouch and within the pouch seem to be important for patterning and cell proliferation (261, 262, 263). Embryological studies in the rat suggest that the programs required for specification of all hormone-producing cell types is completed as Rathke’s pouch closes (around e12 in the mouse).

Concurrent with the appearance of the anterior and intermediate lobes of the pituitary gland, formed from the ventral and dorsal aspects of Rathke’s pouch, respectively, the posterior gland develops from neural ectoderm (Fig. 6Go).


    IV. Expression and Function of POU Domain Factors in the Neuroendocrine System
 Top
 Abstract
 I. Introduction
 II. Structure and...
 III. Development of the...
 IV. Expression and Function...
 V. Relevance of POU...
 References
 
A. Pit-1
1. Pit-1 proteins. The Pit-1 gene encodes a 33-kDa protein composed of an 80-amino acid N terminus that functions as a transactivation domain and a C-terminally located POU domain that is responsible for DNA-binding, homodimerization, and other protein-protein interactions as previously described (80, 264). The N-terminal domain of Pit-1 is rich in hydroxylated amino acids (serines and threonines) and contains tyrosine residues that seem to be critical for transactivation function. Depending on the DNA site, Pit-1 can either bind as a monomer or dimer, which allows selective use of a tyrosine-dependent synergy domain in its N terminus (234).

Several alternatively spliced isoforms of Pit-1 have been described (81, 265, 266, 267, 268). These include Pit-1{beta}, an isoform containing a 26-amino acid insertion, which is conserved among mammals, in position 48 of the N-terminal transactivation domain (265, 266, 269). While Pit-1{beta} is expressed at levels that are 7- to 8-fold lower than that of Pit-1, it has been shown in transient transfection assays that the Pit-1{beta} isoform has distinct properties from Pit-1 (266, 270, 271). Another isoform is Pit-1T, which contains a 14-amino acid insertion at the same location and may play a specific role in TSH{beta} stimulation (268, 272).

As previously described, Pit-1 can also be regulated at a posttranscriptional level. For instance, phosphorylation is reported to lead to decreased or increased DNA binding depending on the DNA-binding site (126, 128). Activin leads to increased Pit-1 phosphorylation that not only decreases DNA binding, but also decreases the stability of Pit-1 (273).

2. Regulation of terminal differentiation. Ontogenic analyses showed that the initial expression of Pit-1 in the caudomedial region of the pituitary gland at e14.5 in the mouse correlated both temporally and spatially with the subsequent activation of the GH, PRL, and TSH{beta} genes (139, 274) (Fig. 6Go). Throughout development and in the adult, Pit-1 expression continues in somatotropes, lactotropes, and thyrotropes (Fig. 6Go). Consistent with a role for Pit-1 in these cell types was the observation that the developmental-specific gene regulatory regions of the GH, PRL, and TSH{beta} genes contain AT-rich elements to which Pit-1 binds and which mediate Pit-1-stimulated activation in transient transfection assays (71, 275, 276). Subsequent analyses of the Pit-1-deficient Snell and Jackson dwarf mice suggested that these in vitro findings are of biological importance because, with the exception of TSH expression in Pit-1-independent rostral tip thyrotropes (72), activation of the GH, PRL, and TSH{beta} genes fails in Pit-1-mutated mice (27) (Fig. 4Go).

In addition to regulating target genes by binding to regulatory regions in close proximity to promoter regions, there are data implicating Pit-1 in regulating locus control regions (LCRs). The human pituitary GH (GH-N) gene contains Pit-1, Zn-15, and Sp1 binding sites in the first 140 bp upstream of the transcription start site. This region, however, is not sufficient for efficient expression in transgenic mice (277) and an LCR appears to be required for efficient and consistent expression of the hGH-N gene. LCRs, which mediate an efficient and position-independent expression of associated genes, are thought to perform their function by establishing open chromosomal domains as well as by acting as enhancers. Two pituitary-specific DNAse-hypersensitive sites were found in a 1.6-kb region located approximately 15 kb upstream of the transcription initiation site (277) and within this region enhancer activity was localized to a 404-bp region (278). This region contains three A/T-rich Pit-1-binding sites that seem to be important for the activity of this LCR in transgenic mice, suggesting that Pit-1 is involved in the enhancer activity of the GH LCR, consistent with a chromatin-mediated developmental role for Pit-1 (279, 280). Interestingly, the A/T-rich Pit-1-binding sites bear some similarity to nuclear matrix anchorage sites (281), but it has been demonstrated that the POU-specific domain of Pit-1 contains information for targeting to the nuclear matrix (282).

3. Regulation of cell proliferation. In addition to regulating expression of the terminal differentiation marker genes GH, PRL, and TSH{beta}, Pit-1 stimulates cell proliferation of pituitary cells, as evidenced in the Snell and Jackson dwarf mice, which are characterized by marked failure in the expansion of somatotropes, lactotropes, and thyrotropes (27). In addition, microinjection of Pit-1 antisense sequences resulted in decreased cell proliferation of GC somotatroph cells (283). Recent findings have suggested three mechanisms involved in Pit-1-induced expansion of pituitary cells. First, experiments with adenovirus suggest that Pit-1 can directly regulate DNA replication in vitro (215). Second, Pit-1 may directly regulate IE genes involved in cell-cycle initiation, such as c-fos (284). It has been shown that Pit-1 expression in PC12 cells, which do not normally express Pit-1, leads to increased c-fos expression. In addition, decrease of Pit-1 protein levels, by means of an antisense strategy, leads to decreased cAMP-induced c-fos promoter activity in pituitary cell lines. Finally, Pit-1 is required for expression of the GHRH receptor, which acts to stimulate proliferation of somatotrophs (74, 75, 285, 286). However, the ontogeny of GHRH receptor mRNA expression, which is highest at 19.5 in the rat with subsequent decrease until postnatal day 12, does not correlate with that of Pit-1, indicating that other factors, in addition to Pit-1, are important for GHRH receptor expression (287). Pit-1 binding sites have also been described in the TRH receptor gene regulatory region (78), suggesting a possible mechanism for Pit-1 regulation of proliferation of thyrotropes.

4. Regulation of Pit-1 gene expression. The Pit-1 gene is located on chromosomes 3p11 and 16 in humans and mice, respectively. In the mouse, the Pit-1 gene is initially activated on e13.5–14 under control of a specific early enhancer that remains to be precisely characterized, but appears to be located between –5.1 and –10.2 kb upstream of the start site (288). From e16.5, Pit-1 expression requires a different autoregulated distal enhancer, located 10 kb upstream of the Pit-1 start site (70, 288). The distal enhancer contains three functional Pit-1 binding sites, a vitamin D receptor-binding site, and an retinoic acid response element (RARE) that mediates a Pit-1-dependent RAR induction (70). In the Snell dwarf mouse, Pit-1 gene expression at e14.5 is initiated normally but is extinguished in the perinatal period, apparently due to failure of autoregulation (27). The proximal promoter region of the Pit-1 gene also contains Pit-1 binding sites (68, 69). Mutations in the transcription factor gene Prop-1 in the Ames dwarf mouse lead to a failure in the initial activation of Pit-1 gene expression (289); this effect, however, may be indirect. The transcription factor GATA-2 may be responsible for restricting Pit-1 gene expression from ventral cell types by repressing the Pit-1 early enhancer (151).

5. Restriction and selective facilitation of Pit-1 action. Pit-1 is expressed in three distinct cell types in the anterior pituitary gland, and in each of these cell types it seems to be required for the expression of the characteristic hormone-encoding gene (Fig. 4Go). Therefore, there must be mechanisms in place that limit the function of Pit-1 to prevent it, for example, from activating the GH gene in thyrotropes. There are some data suggesting that sequences in the target genes mediate active repression in heterologous pituitary cells (290, 291). The abundance of evidence, however, suggests that a complex combinatorial code based on synergistic interactions with other transcription factors is responsible for cell-specific target gene activation by Pit-1.

The GH promoter is synergistically regulated by Pit-1 and TR/RXR or RAR/RXR (136, 292), apparently based on protein-protein interaction where Pit-1 can interact strongly with RXR but also to a lesser extent with TR and RAR (135). The synergism between Pit-1 and TR depends, in part, on Pit-1 residues that when mutated have no effect on Pit-1 acting alone. Thus, while the synergism amplifies the intrinsic activity of Pit-1, there are also functions that are specific to synergistic activation (134). Other transcription factors that bind to the GH promoter are a zinc finger transcription factor, Zn-15, which is required for activation of the GH gene (293) and C/EBP{alpha} (294), both binding to and activating the rat GH promoter in a synergistic fashion with Pit-1.

The PRL gene promoter is regulated by estrogens only when it is bound both by Pit-1 and the ER, and this synergistic regulation depends on the intact AF-2 domain of ER (137, 139, 141, 295, 296). There is evidence for direct interaction between ER and Pit-1 that is estrogen dependent (140). The Pit-1/ER synergism is modulated by nuclear receptor coactivators with RIP140 inhibiting and SRC-1 and GRIP1 stimulating (295). In addition, there is strong synergism between Pit-1 and Pitx1 (143, 144) and Pitx2 (146) on the PRL promoter.

Members of the ETS family of transcription factors can bind to a composite Ets-1/Pit-1 binding site in the rat PRL promoter (148, 297, 298, 299). Synergistic gene activation between Pit-1 and Ets-1 may be important for basal activity and in mediating signals from growth factors and the Ras/mitogen-activated protein kinase (MAPK) pathway to the PRL gene (297, 298, 299). The synergistic gene activation correlates with direct Pit-1-Ets-1 protein-protein interaction; this interaction is specific and not observed with Ets-2 (148). In addition, ETS factors do not bind to or activate the GH promoter and are therefore good candidates for factors contributing to the combinatorial control that is specific for PRL gene expression (148).

ETS-2 repressor factor (ERF) contains an ETS DNA binding domain and a C-terminal repressor domain (300). This factor can bind to the PRL promoter and inhibit its activity. In cell lines, overexpression of ERF blocks induction of PRL transcription by protein kinase A and acts in an additive manner with dopamine to suppress PRL promoter activity, suggesting that dopamine and ERF may function by complementary mechanisms to suppress PRL promoter activity. In addition, it can block the cooperative activation of PRL gene expression by Pit-1 and ETs-1. ERF seems to act by inhibiting Pit-1 binding to the PRL regulatory elements and could be responsible for cell-specific repression of the PRL gene.

Studies on the human TSH{beta} promoter suggest that there are functional interactions between Pit-1 and AP-1, with both factors binding to DNA, resulting in synergistic transcriptional regulation (301). The activity of the transcription factor GATA-2, which appears to be required for the formation of both thyrotrope and gonadotrope cell types, can be modulated by Pit-1 (150, 151). The presence of Pit-1 represses the gonadotrope phenotype via direct interactions with GATA-2, inhibiting its binding to cognate DNA sites important for generation of the gonadotrope phenotype (151) (Fig. 2AGo). Pit-1 can thus inhibit promoters that contain GATA-2 binding sites and no Pit-1 binding sites, such as the gonadotrope-specific SF-1 promoter. In contrast, Pit-1 can also synergize with GATA-2 to promote the thyrotrope phenotype on promoters containing adjacent Pit-1 and GATA-2 sites, such as the thyrotrope-specific TSH{beta} promoter (150, 151) (Fig. 2AGo).

6. The role of Pit-1 in hormonal regulation of target genes. In addition to a role in regulating the appearance of cell types and expression of target genes during development, there is evidence that Pit-1 functions in the homeostatic hormonal regulation of gene expression in the anterior pituitary gland (302). Experimental results suggest that Pit-1 participates in pathways for acute regulation of the GH, PRL, and TSH{beta} genes.

GH gene regulation is stimulated by GHRH released into the tuberoinfundibular system and acting on the GHRH receptor located on somatotropes (303). This G protein-coupled transmembrane receptor in turns acts by stimulating the production of cAMP and activating protein kinase A. While there are cAMP response elements (CREs) within the human GH promoter, experiments suggest that the protein kinase A signal is mediated by phosphorylation of CBP associating with and acting as a cofactor for Pit-1 (Fig. 3Go).

Transcription of the PRL gene is regulated by dopamine, which acts by reducing intracellular cAMP concentration and lowering protein kinase A activity (304). This response is unusual in that it does not appear to require CREB and CREs and instead may be mediated by the most proximal Pit-1-binding site of the rat PRL promoter. Mutagenesis of the three phosphoacceptor sites in the POU domain of Pit-1 showed that these are not required for hormonal regulation of PRL (127, 305), suggesting that other proteins binding to this site or Pit-1-associated cofactors may be the substrate. Recently it was shown that Pit-1 and CBP synergistically regulate the PRL promoter, suggesting that association of CBP with Pit-1 may be responsible for cAMP regulation of the PRL gene (152) (Fig. 3Go). It has also been shown that the cAMP response is enhanced by Oct-1 and the Pit-1{beta} isoform (306), suggesting that Oct-1 can act as a protein kinase A signaling cofactor. TRH, which is known to regulate PRL gene transcription, can stimulate PRL reporter plasmids in GH3 cells, apparently also via Pit-1 interacting with its binding sites in the PRL promoter (307, 308).

Glucocorticoids mediate negative regulation of the human PRL promoter. This inhibition, which requires both Pit-1 and GR, is conferred by a gene-regulatory region containing Pit-1 binding sites but no GRE (142). The inhibition does not require GR to bind to DNA, and coimmunoprecipitation studies show that GR and Pit-1 interact.

B. Oct-1
Oct-1 is ubiquitously expressed (309) and encodes a 100-kDa protein that has been implicated in the cell cycle-regulated expression of histone H2B (86) and in the ubiquitous expression of small nuclear RNA genes (84, 85). Based on these data, and the fact that Oct-1 can stimulate DNA replication (212, 310, 311), it has been suggested that Oct-1 may play an important role in regulating cell proliferation. However, there is also a large amount of data suggesting that Oct-1 may play roles in regulating expression of cellular genes not associated with cellular proliferation. No knockout study of Oct-1 has been published.

1. Oct-1 in GnRH gene regulation. Studies in the brain have suggested that Oct-1 is not highly expressed in neurons, especially nondividing mature neurons (312), and is mostly found in glial cells (313). However, there is evidence suggesting that Oct-1 may be directly involved in neuroendocrine gene regulation. Based on data from work with the hypothalamic cell line GT1–7, a model for GnRH-expressing neurons, the rat GnRH gene contains two regulatory regions: an evolutionary conserved proximal promoter region located between—170 and –1, and a 300-bp distal enhancer located approximately 1.7 kb upstream of the start site (29, 314). The proximal promoter of the rat GnRH gene, which is critical for regulated expression of the GnRH gene by protein kinase C (29, 314) and progesterone (315), is bound by several nuclear factors in the GT1–7 cell line (29). In addition, this region contains at least two octamer-binding elements that are critical for transcription directed by the GnRH promoter in GT1–7 cells (29). Two octamer sites are also found in the rat GnRH neuron-specific enhancer located 1.7 kb upstream of the promoter, and the activity of the enhancer is critically dependent on Oct-1 binding to these sites (28). These data suggest that Oct-1 plays critical roles in regulation of GnRH transcription, by interacting with both enhancer and proximal promoter sequences, perhaps through homotypic interactions between Oct-1 bound to the enhancer and the promoter (28, 29).

In the GT1–7 cell line, GnRH gene expression is repressed by the NO/cGMP signal transduction pathway (316). This repression, which is mediated by the 300-bp distal enhancer, is obliterated when either an Oct-1 or a C/EBP binding site is mutated, suggesting that these factors play a role in the NO/cGMP pathway (317). Consistent with this observation are experiments showing that NO analogs increase Oct-1 binding to octamer sites in GT1–7 cells (317). However, this effect of NO on Oct-1 binding may be cell-specific because in cultured vascular smooth muscle cells, NO inhibits Oct-1 DNA binding (318). Such cell-specific effects of NO might be due to differential activation of signal transduction pathways in different cell types.

As previously described, experiments with the mouse GnRH promoter in the GT1–7 cell line suggest that GR can confer negative regulation on this promoter by associating with Oct-1 bound to one of the octamer elements (158, 319, 320). Apparently, this particular Oct-1 binding site imposes conformational changes that allow docking of GR to Oct-1 and repression of transcription (158).

2. Oct-1 in vasoactive intestinal peptide (VIP) gene regulation. Oct-1 has also been implicated in regulation of VIP, which is widely distributed throughout the central and peripheral nervous system, including the hypothalamus and anterior pituitary gland (321, 322). VIP can function as a neuromodulator, growth regulator, and neuroendocrine releasing factor. Experiments using subclones from the SK-N-SH neuroblastoma cell line to study the VIP promoter have identified an upstream tissue-specific element (TSE), located between –4.6 and –4.0 from the start site in addition to a proximal promoter element containing a CRE. The 425-bp TSE contains two octamer sites, similar to those found in the GnRH neuronal-specific enhancer, both of which are important for expression (30). Both elements bound Oct-1 with the upstream element also binding Oct-2 in neuroblastoma cell extracts.

3. Oct-1 and TSH{beta} gene silencing. Oct-1 has been implicated in silencing of the hTSH{beta} gene in heterologous cells (291). Kim et al. localized an AT-rich region between –128 and –480 bp upstream of the start site. This element was bound by Oct-1 in multiple locations, and silencing was mediated by the alanine-rich C-terminal domain of Oct-1. Oct-1, again acting through multiple binding sites, has also been implicated in silencing of the 3{alpha}-hydroxysteroid/dihydrodiol dehydrogenase gene (323). In addition, a silencer in the B cell-specific B29 (Ig{beta}) gene is an AT-rich region shown to bind Oct-1 and Oct-2 (324). Together, these studies and the fact that such AT-rich regions may serve as nuclear matrix attachment sites suggest that Oct-1 may have a general role in gene silencing. Consistent with this idea are observations that a significant amount of Oct-1 is found in the nuclear matrix fraction of nuclei (325, 326).

C. Oct-2
Oct-2 encodes a 60-kDa protein, preferentially expressed in B lymphocytes, especially in the most mature cell types, as well as in the developing and adult nervous system (313, 327, 328). In contrast to the widespread embryonic nervous system expression, Oct-2 is confined to specific areas in the adult, which include the suprachiasmatic and medial mammillary nuclei, hippocampus, olfactory tract, and the olfactory bulb (313). Oct-2 proteins are present in both neuronal and oligodendroglial cells, but are more abundant in glial cells (313). At least eight alternatively spliced mRNAs have been detected (329), and there is evidence that the different splice variants, which are differentially expressed to a certain extent, may have different functions (327, 330). In addition to the most predominant form, Oct-2A, two of the splice variants, Oct-2.5 and mini-Oct, are expressed at high levels in neural tissue (327). Oct-2 has also been detected in intestine, testes, and kidney (313).

1. Oct-2 gene-deleted mice. Oct-2 gene-deleted mice develop normally, including B cell development, but show an abnormal function of mature B lymphocytes with defective immunoglobin secretion in response to polyclonal antigens (331, 332). These mice die within hours of birth, and while no gross structural abnormalities within the nervous system have been described (333), it has been suggested that the cause of death may be abnormalities in the nervous system (332).

2. Oct-2 in GnRH regulation. Other experiments have implicated Oct-2 in the regulation of GnRH gene expression and the onset of puberty (31). While transsynaptic regulation of GnRH neurons is clearly important for the onset of puberty and regulation of reproduction, there is also evidence for GnRH neural regulation by astroglial cells within the hypothalamus. Lesions of the anterior hypothalamus lead to precocious puberty apparently caused by increased expression of TGF{alpha} by astrocytes formed in response to the lesion. TGF{alpha} is involved in stimulatory control of GnRH secretion and mimics some of the events in normal puberty. It has been demonstrated that in both lesion-induced puberty and normal puberty there is increased expression of Oct-2a and Oct-2c in the hypothalamus. Both Oct-2 forms can transactivate the TGF{alpha} gene promoter, and inhibition of Oct-2 synthesis with antisense technology reduces TGF{alpha} expression and the onset of puberty. These results suggest that the Oct-2 gene is an important component of a glia-to-neuron signal pathway leading to the onset of female puberty in mammals (31). Since Oct-2 (-/-) mice die around the time of birth, a more rigorous testing of this hypothesis will require the use of a tissue-specific Oct-2 knockout.

D. Overview of expression of Brn-1, Brn-2, Brn-4, and Tst-1 in the neuroendocrine system
Several studies have described the expression patterns of class III POU factors (97, 256, 328, 334, 335, 336). At e10 to e11, Brn-1, Brn-2, and Brn-4 are expressed widely in the nervous system, including in the primordium of the endocrine hypothalamus adjacent to the third ventricle (328). By e14, four separate rostrocaudally arranged areas (corresponding to the preoptic, anterior, ventromedial, and mammillary nuclei) of the hypothalamus are labeled with Brn-2 and Brn-1 (256). At that time, both Brn-2 and Brn-4, but not Brn-1, are colocalized in the region of the developing PVH and SON and Brn-4 expression extends ventrally to potential precursors of the anterior hypothalamus. Brn-1-expressing cells are located immediately dorsolaterally in the presumptive zona incerta and in a dorsoventral stripe lateral to Brn-4-expressing cells. In contrast to the nearly identical widespread expression pattern of Brn-1 and Brn-2 in the developing nervous system, Tst-1 has restricted expression in the developing embryo, but shows dense hybridization signal in the mammillary region at e13. Tst-1 exhibits a much more widespread expression pattern in the adult (256) but is excluded from the hypothalamus.

Both Brn-2 and Brn-4 are expressed at high levels in the PVH and SON of the mature hypothalamus (37, 38, 328, 334, 335). These nuclei contain the parvocellular neurons that synthesize high levels of CRH and the magnocellular neurons that synthesize arginine vasopressin (AVP) and OT (Fig. 5Go). Double labeling studies show that Brn-2 is coexpressed with each of these neuropeptides, but not in a significant number of parvocellular neurons that produce TRH (38). Double labeling experiments show that Brn-4 is not expressed in OT containing neurons of the PVN and SON, but is present in the magnocellular neurons of the PVN and SON that contain dynorphin and vasopressin (335). Brn-2 levels in the PVH in response to ether stress have been studied, and it was found that Brn-2 levels were unchanged (337).

The early neuronal expression of Brn-2, Brn-1, and Brn-4 has suggested a role for these factors in early neurogenesis (50, 328). Multipotential stem cells in the central nervous system are characterized by the expression of the intermediate filament protein nestin and the brain fatty acid binding protein (B-FABP). Regulatory regions of both genes, mapped in transgenic mice, contain POU binding sites close to hormone response elements (HRE), both of which are essential for expression of these stem cell markers (338). In the rat nestin gene, the POU site is recognized by the class III POU proteins Brn-1, Brn-2, Brn-4, and Tst-1 and is critical for general central nervous system (CNS) expression, whereas the HRE is required for full expression in the anterior CNS. In the B-FABP gene a composite POU/Pbx site is essential for neuroepithelial expression. This site can bind Pbx-1, Brn-1, and Brn-2 in CNS extracts, suggesting the possibility that expression of class III POU domain factors may define the stem cell state. Exit from the stem cell state is indeed characterized by changes in expression with many class III genes being turned off and Brn-5 turned on (50, 339). So far, gene deletion experiments of Brn-2, Brn-4, and Tst-1 have shown no early defects consistent with such a model, indicating that either class III factors do not play important roles in early neural development or that redundancy between different members has prevented an observable phenotype in mice deleted for single class III genes.

As described below, with the exception of Brn-1, knockout experiments for all individual members of the class III POU factors have been reported.

E. Brn-2
Deletion of the Brn-2 gene in mice has provided the best evidence for the involvement of class III POU domain factors in neuroendocrine development and function (37, 38). Brn-2 (-/-) mice are born normally but exhibit a decrease in size and weight from postnatal day (p) 3. Most die before p6 and exhibit a marked decrease in brown adipose tissue, consistent with severe malnutrition. Analyses showed dramatic hypothalamic/posterior pituitary gland abnormalities, but no obvious defects outside the hypothalamus (Fig. 5Go). Among the most striking findings was a complete lack of CRH expression in parvocellular neurons of the PVH. This effect was extremely site specific because CRH expression was normal in other regions of the brain. In addition, parvocellular neurons of the PVH that produce TRH, but do not express Brn-2, were not affected. Further, OT and AVP expression was absent from the magnocellular neurons of the PVH and SON, but AVP expression in the non-Brn-2expressing cells of the suprachiasmatic nucleus was maintained normally, again indicating that the defects were cell specific (38). Similarly, anterior periventricular neurons that produce somatostatin and arcuate neurons that produce GHRH, which do not normally express Brn-2, were not affected. The lack of abnormalities in cells of the hypothalamus that do not express Brn-2 suggests that the phenotype of the Brn-2 (-/-) mouse is due to cell-autonomous effects. By e19.5, a striking decrease in cellularity of the PVH and SON was also observed.

The developing posterior pituitary gland in Brn-2 (-/-) mice appears to be normal until e16.5 when axonal projections from magnocellular neurons fail to make contact (37, 38). By e19 Brn-2 (-/-) mice show complete loss of pituicytes and a fold of the intermediate lobe instead fills the space normally occupied by the posterior lobe of the pituitary gland. Therefore, Brn-2 appears to be essential for magnocellular neurons to invade the posterior pituitary gland structure. These axons are then required for the survival of the pituicytes of the posterior pituitary gland. Surprisingly, despite the lack of CRH and AVP, ACTH expression in the pituitary gland of Brn-2 (-/-) mice is normal, as are the adrenal glands. This finding may indicate that alternative mechanisms are involved in regulating the ACTH/cortisol axis in the mouse.

Thus, the Brn-2 gene is required for the terminal differentiation and survival of cell types that compose the magnocellular system and one of the parvocellular cell types that comprise the central control of the pituitary-adrenal axis (Fig. 5Go). Detailed ontogenic analyses suggest that precursors for neurons of the PVH and SON die around e12.5 during migration (37). While the Brn-2 (-/-) mice show a severe phenotype in the PVH and SO, no obvious abnormalities are observed in the vast majority of neurons where Brn-2 is expressed. It has been proposed that overlapping expression with other class III POU factors, such as Brn-1, may provide redundancy to Brn-2 function in some neurons. However, in the PVH and SO, Brn-4 is clearly incapable of compensating for the loss of Brn-2. A proof for a model proposing both overlapping and specific neuroendocrine functions for each of the class III POU factors will require the analyses of double and triple mouse mutants.

While no morphological changes were observed in Brn-2 heterozygous (+/-) mice, these mice only expressed half the level of Brn-2 compared with wild-type mice. Intriguingly, this decrease in Brn-2 levels correlated with 50% reduction in the levels of AVP and OT in Brn-2 (+/-) mice (37). These results suggest that Brn-2 levels are limiting for the expression of AVP and OT and that in addition to a developmental function in the specification of AVP and OT-producing neurons, Brn-2 has a direct role in regulating the expression of these genes in the adult. Consistent with this notion, several elements capable of binding class III POU factors have been identified in the region –1,535 to –1,270 in the rat OT gene (340). In addition, the 5'-region of the CRF gene contains Brn-2-binding sites (63), which seem to be responsible for the activation of the CRF promoter (38). Further support for this model comes from experiments with the neuroblastoma cell line BE(2)-M17, where retinoic acid induces expression of CRF. Expression of Brn-2 antisense RNA abrogates this response, suggesting that Brn-2 acts in a pathway mediating retinoic acid-induced CRF expression in terminally differentiated neurons (341).

The basic helix-loop-helix (bHLH)-PAS transcription factor SIM1 is expressed in three hypothalamic nuclei during development: the PVN, the SO, and the anterior periventricular nucleus. In SIM1 (-/-) mice, the hypothalamus is hypocellular and neurons expressing OT, vasopressin, TRH, ACTH, and somatostatin (SS) are absent from these nuclei (342). Thus, the phenotype of SIM1 gene-deleted mice is overlapping but more severe than that of Brn-2 gene-deleted mice. Evidence suggests that SIM1 functions to maintain Brn-2 expression, and part of the observed phenotype may be due to loss of Brn-2 expression (342). The relationship between SIM1 and Brn-2 in the hypothalamus is therefore somewhat analogous to the relationship between Prop1 and Pit-1 in the anterior lobe of the pituitary gland.

F. Brn-4
Deletion of the Brn-4 gene in mice resulted in multiple developmental defects in the inner ear, causing deafness, but no detectable defects in the development or function of the central nervous system (343, 344). The inner ear phenotype is consistent with the expression of Brn-4 in the otic vesicle and derived structures. The lack of phenotype in most neurons expressing Brn-4 suggests the possibility that related POU domain factors may function on Brn-4-responsive genes in the absence of functional Brn-4.

Brn-4, which is highly expressed in proglucagon-expressing cells of the pancreas, binds to the G1 promoter element of the proglucagon promoter, and in transient transfection experiments, Brn-4 appears to be a major regulator of proglucagon gene expression (107). It is unclear whether neuronal expression of proglucagon is regulated by the same mechanisms. The biological relevance of these in vitro studies is unknown because analysis of pancreatic structure or function in Brn-4 (-/-) mice has yet to be presented. Brn-4 has also been implicated in the regulation of striatal D1A dopamine receptor gene transcription (106).

G. Tst-1
In addition to the previously described neuronal expression in the hypothalamus, Tst-1 is prominently expressed in myelin-forming glia of the central and peripheral nervous system during a period of rapid cell division (97, 98, 99, 328, 345, 346). In cultured Schwann cells where cAMP induces the expression of myelin-specific genes, Tst-1 gene expression is also induced, preceding the induction of myelin-specific markers (345). In addition, Tst-1 is expressed in embryonic stem cells and in the developing nervous system (97). Expression in the brain is prominent in certain areas of the telencephalon, mesencephalon, brain stem, cortex anlagen, and in the developing colliculi (97, 328).

1. Tst-1 gene-deleted mice. Deletion of the Tst-1 gene in mice produces a severe defect in peripheral myelination by arresting Schwann cell maturation before axonal wrapping (347, 348). Most neuronal development appears to progress normally except for the phrenic nucleus, which is disrupted, and neurons of the nucleus of the lateral olfactory tract, which mismigrate. Most Tst-1 (-/-) mice die soon after birth but the occasional survivor is severely runted, consistent with a possible undefined defect in neuroendocrine function.

2. Tst-1 in GnRH gene regulation. Tst-1 transcripts are found in the neuronal cell line GT1–7, which produces GnRH, and in a subset of GnRH neurons in the hypothalamus of prepubertal female rats. In vitro studies using transfected cell lines have shown that Tst-1 can repress the GnRH promoter, apparently by binding to three sites in the promoter (100). Since neurons capable of synthesizing GnRH seem to fluctuate between GnRH positivity and negativity depending on the reproductive cycle, it has been proposed that Tst-1 can determine the ratio of phenotypically active and inactive GnRH neurons during postnatal life (100).

H. Oct-3
The Oct-3 gene is expressed in male and female primordial germ cells, unfertilized oocytes (but not spermatocytes), and embryonic stem cells of the preimplantation embryo (51, 53, 349). The Oct-3 protein is also found in totipotent and pluripotent cells of the inner cell mass of the pregastrulation embryo, but not in the trophoectoderm. Expression of Oct-3 is required for the formation of totipotent cells of the embryo since mutation of the Oct-3 gene in mice causes all cells of the embryo to acquire a trophoblastic cell fate (49).

Oct-3 is expressed in the early embryo with expression in the headfold ectoderm extinguished around e8.5, when neural induction occurs (349), suggesting that its disappearance might be important for early neural induction (50). The embryonic carcinoma P19 cell model for neural induction is consistent with this idea. Treatment with RA, which produces a neuronal like phenotype, leads to down-regulation of Oct-3 while forced expression of Oct-3 in certain differentiated P19 cells specifically represses expression of Brn-2 and nestin. Together, these data suggest the possibility that POU domain factors may control the acquisition and loss of stem cell characteristics in the CNS (50). Oct-3 is not expressed in the hypothalamus or pituitary gland and is not likely to play later roles in the neuroendocrine system.

I. Brn-5 and RPF-1
Brn-5 exhibits widespread expression in neurons and tissues outside the nervous system (56, 57, 58, 350, 351). Within the hypothalamus, expression of Brn-5 is reported in the mammillary nucleus and ventral area (339). Brn-5 is also expressed in the anterior pituitary gland (56). During development, predominant expression is found in postmitotic neurons and not in proliferating neuronal precursors, suggesting that Brn-5 may have a role in regulating the postmitotic fate of these cells (339). In addition, ectopic expression of Brn-5 in dividing NG108–15 cells, a neuroblastoma/glioma hybrid cell line, reduces proliferating cell nuclear antigen (PCNA) mRNA levels and inhibits DNA synthesis, suggesting the possibility that Brn-5 may suppress continued cell proliferation (352). No specific function has been proposed for Brn-5 in the neuroendocrine system and a knockout study has not been reported.

The second class VI POU factor, RPF-1, is expressed only within the CNS, where its expression is restricted to the medical habenulla, to a dispersed population of neurons in the dorsal hypothalamus, and to subsets of ganglion and amacrine cells in the retina (59). No specific function has been proposed for RPF-1 in the hypothalamus, and a knockout study has not been reported.


    V. Relevance of POU Domain Factors to Diseases of the Neuroendocrine System
 Top
 Abstract
 I. Introduction
 II. Structure and...
 III. Development of the...
 IV. Expression and Function...
 V. Relevance of POU...
 References
 
A. Pit-1 mutations as a cause of combined pituitary hormone deficiency in humans
Several Pit-1 gene mutations that result in combined pituitary hormone deficiency (CPHD) have been described in humans (353, 354, 355, 356) (Table 8Go). Clinically, patients usually have serum GH and PRL levels that are below detection in standard assays, indicating loss of all secretory function in somatotropes and lactotropes. Initially, some patients have detectable TSH levels, but ultimately all patients develop secondary hypothyroidism (Fig. 4Go). In other cases, a severe central hypothyroidism has been diagnosed at birth (357). NMR studies have shown variable normal or small anterior pituitary glands.


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Table 8. Overview of human Pit-1 mutations

 
From a genetic standpoint, these mutations fall into one of two general classes: autosomal recessive and dominant (353, 354, 355) (Table 8Go). Those inherited in an autosomal recessive pattern are often, but not always, due to disruption of DNA binding of Pit-1. Examples include Arg172Stop, Glu250Stop, Ala158Pro, Arg143Gln, Phe135Cys, and Pro239Ser. These mutations are similar to the Pit-1 mutation in the Snell dwarf mouse where a tryptophan at residue 261 is replaced with cysteine. A tryptophan at this position is critical for DNA binding and conserved in all POU-H domains. Other mutations, which occur both familially and in sporadic cases, are inherited as dominant traits and therefore clinically evident in heterozygous individuals. These mutations, like Arg271Trp, Pro14Leu, and Pro24Leu, tend to retain DNA-binding ability but somehow dominantly interfere with the function of wild-type Pit-1 transcribed from the other allele.

The Ala158Pro Pit-1 mutation, affecting the second helix of the POU-S domain (Fig. 7Go), was described in two homozygous Dutch families with severe GH and PRL deficiency but mild hypothyroidism (358). An NMR study showed normal size anterior pituitary glands in the two affected patients (358). The Ala158Pro protein binds normally to cognate DNA sites but is transcriptionally inactive on the GH, PRL, and Pit-1 promoters. Apparently, this region of the Pit-1 molecule is crucial for transactivation, either directly or through recruitment of coactivators.



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Figure 7. Selective human Pit-1 mutations. A three-dimensional schematic of a Pit-1 monomer bound to its DNA site. The locations of selective human Pit-1 mutations are indicated. See text for discussion of each mutation.

 
The homozygous Phe135Cys Pit-1 mutation was found in four of eight siblings born to healthy consanguineous parents. This mutation affects a hydrophobic region of the first helix of the POU-S domain. All four patients presented with complete GH deficiency, later developed central hypothyroidism, and were found to have undetectable PRL levels. One of the patients had a successful NMR study at age 18, which showed a hypoplastic pituitary (359).

A homozygous Pit-1 mutation, Pro239Ser, is located at the beginning of the second {alpha}-helix of the POU-H domain, in a position that is strictly conserved among all POU proteins. The Pro239Ser protein has been reported to bind to DNA, but fails to activate the GH promoter. This mutation has been reported in seven individuals from three unrelated Middle Eastern families (360).

An isolated case has been described in which a patient harbored compound heterozygous mutations (361). One mutation, Arg172Stop (Fig. 7Go), results in a protein lacking part of the POU-S and all of the POU-H domains, predicting a complete loss of function. The other mutation, Glu174Gly, affects the DNA-recognition helix of the POU-S domain. This protein is reported to have drastically decreased affinity for DNA (361). The Arg172Stop mutation has also been described in a homozygous form (362).

Other human Pit-1 mutations have been described, but not extensively characterized. These include a homozygous mutation, Arg143Gln (Fig. 7Go), found in a child of consanguineous parents. This mutation is located within the first helix of the POU-S domain and presumably disrupts a basic region important for DNA binding (363). Glu250Stop (Fig. 7Go) has been described in a single homozygous patient and would delete the DNA-recognition helix of the POU-H domain of Pit-1, thus interfering with DNA binding (364).

A heterozygous Arg271Trp mutation (Fig. 7Go), found both in sporadic and familial cases, seems to be a common cause of Pit-1 dysfunction, with at least 11 cases reported in unrelated families of diverse ethnic backgrounds (357, 363, 365, 366, 367, 368, 369). The Arg271Trp mutant protein, which is altered in the basic region of the DNA-recognition helix of the homeodomain, binds DNA with normal or increased affinity but fails to stimulate transcription from Pit-1-responsive promoters and acts as a dominant repressor of transcription (366). One patient was described to have abnormal facial features with prominent forehead, marked midfacial hypoplasia with depressed nasal bridge, deep-set eyes, and a short nose with anteverted nostrils (365). These changes, however, are probably not specific for Pit-1 mutations because similar facial features, sometimes found in GH deficiency of other etiology, become less prominent with GH therapy. Interestingly, within a family some individuals harboring the Arg271Trp mutation may be clinically normal, possibly due to preferential expression from the normal Pit-1 allele (367).

Other less well characterized dominant mutations include Pro14Leu and Pro24Leu, which are located within the transactivation domain of Pit-1 and found in heterozygous individuals (363, 370, 371).

An unusual heterozygous mutation, Lys216Glu, was described in a single patient. This mutation has no effect on DNA binding nor does it directly interfere with GH or PRL gene expression. Instead it blocks RA induction of Pit-1 gene expression. Cohen et al. (372) suggest that this mutation interferes with RA-induced activation of the Pit-1 gene during a crucial period of development (372). This mutation affects the C-terminal part of the linker between the POU-S and POU-H domains and therefore may disrupt important protein-protein interactions between Pit-1 and other transcription factors (372).

The Prop1 (Prophet of Pit-1) gene acts upstream of Pit-1 in the pituitary developmental pathway as evidenced by the failure of effective Pit-1 gene activation in the Prop-1 defective Ames mouse (289, 373). However, mutations in the human Prop1 gene lead to a CPHD in humans that is different in several respects from CPHD caused by Pit-1 mutations (353, 355). First, the clinical presentation is more variable and while all patients ultimately develop GH, PRL, TSH, and gonadotropin deficiency, the age of diagnosis varies significantly. Apparently, Prop1 mutated individuals can have remnant secretion of GH and PRL. Second, gonadotropin deficiency, which is not found in Pit-1- mutated individuals, is common in Prop1-mutated patients. Third, one family with a Prop1 deletion has been found to have ACTH deficiency (374). Fourth, while most Pit-1 and Prop1 mutated individuals will have small anterior pituitary glands on NMR examination, occasionally Prop1 patients develop parasellar tissue masses that regress over time.

Thus, whereas the phenotypes resulting from mutations in the human Pit-1 gene seem to mirror quite well the phenotype of the Pit-1-mutated Snell dwarf mouse, mutations in the human Prop1 gene can lead to a phenotype distinct from the Prop1-mutated Ames dwarf mouse. This observation has been interpreted that, in contrast to human disease mutations, the Prop1 mutation in the Ames dwarf is a hypomorph, leading to a partial loss of function. Regardless of the explanation, these data suggest that in humans, the Prop1 gene plays a role in the differentiation of at least gonadotropes, in addition to acting upstream of Pit-1 in generating the Pit-1-dependent cell lineages.

B. Brn-4 mutations in humans
Brn-4 mutations have been described in humans where they cause an X-linked nonsyndromic mixed deafness disorder referred to as DFN3 (343, 375). As in the Brn-4 (-/-) mouse, no metabolic changes have been reported in these individuals, but specific metabolic tests might be needed to detect subtle differences.

C. Potential implications for other diseases
1. Pituitary adenomas. Several studies on the expression of Pit-1 in pituitary tumors have been published, showing Pit-1 commonly expressed in GH-, PRL-, and TSH{beta}-secreting tumors (376, 377, 378, 379, 380, 381, 382, 383, 384). No major abnormalities in the amount or form of Pit-1 transcripts have been observed in these tumors, and Pit-1 mRNA levels seem to be similar in somatotrope and lactotrope adenomas (382, 385). In addition, Pit-1 is expressed in many clinically nonfunctioning pituitary adenomas, but in most of those, mRNAs for GH, PRL, or TSH{beta} were also found (381). Pit-1 transcripts have also been found in ACTH-secreting tumors, again with expression seeming to correlate with GH-, PRL-, or TSH{beta}-expressing cells found in these tumors (381). Since Pit-1 has been implicated in proliferation of certain pituitary cell types during development, it is reasonable to propose that Pit-1 is at least a component in the pathways leading to the formation of these tumors.

Tuberoinfundibular dopamine, acting through dopamine D2 receptors, tonically inhibits PRL synthesis and secretion from lactotropes. As previously described, the dopamine signal may ultimately be transmitted through Pit-1 action on the regulatory region of the PRL gene (386, 387). Female mice deleted for the dopamine D2 receptor develop lactotroph hyperplasia and prolactinomas. Male mice deleted for the dopamine D2 receptor develop prolactinomas without any accompanying hyperplasia. In each case, these adenomas showed both Pit-1 and ER expression, suggesting that Pit-1 may participate in the pathway ultimately leading to experimental prolactinomas (388). In humans there seems to be a correlation between D2 receptor mRNA and Pit-1 mRNA levels in prolactinomas (382, 389).

Activating mutations in the G protein {alpha}(S) subunit, the gsp oncogene, may be responsible for as many as 40% of somatotropinomas (389). In transient transfection assays, a constitutively active {alpha}(S) subunit stimulates expression from a reporter construct under the control of the proximal 200 bp of the Pit-1 promoter. Full induction seems to depend on Pit-1 and CREB, which both bind to this region (390). Thus the overactivity of protein kinase A in this system may increase Pit-1 levels. In addition, the constitutive activation of this pathway may directly stimulate target genes such as the GH and PRL promoters (391). As previously described, this action seems to be mediated through Pit-1 binding sites in the GH gene, perhaps by direct interaction of CBP with Pit-1 (153, 303).

While there is evidence implicating Pit-1 as a target of signaling pathways that lead to pituitary adenoma formation in humans and mice (392), no specific abnormalities in Pit-1 expression or function implying a more causative role have been associated with the genesis of human pituitary tumors. One could hypothesize that putative activating mutations of Pit-1 may contribute to hormone-secreting tumor formation. However, even if Pit-1 abnormalities do not cause tumor formation, understanding Pit-1 function may help in designing strategies to control the secretion and proliferation of pituitary tumors of the somatomammotrope lineage.

2. Developmental defects. Septo-optic dysplasias, characterized by optic nerve hypoplasias, pituitary gland hypoplasias, and other midline abnormalities of the CNS, such as absence of the corpus callosum and septum pellucidum, are most likely caused by mutations in genes that act earlier than POU domain factors in the development of the hypothalamic/pituitary axes. Indeed, at least some cases are caused by a mutation in the paired like homeobox gene, Rpx/Hesx1, which acts early in pituitary development (393, 394).

3. Hypothalamic disease. It is clear that the hypothalamus is important for several symptoms and diseases that fall outside classic neuroendocrine disorders. These include psychiatric diseases such as depression (395), disturbances in the biological clock (396), and obesity and other eating disorders (397). So far no such abnormalities have been demonstrated in mice deleted for POU factors highly expressed in the hypothalamus.


    Acknowledgments
 
We thank Tod Sugihara, Aimee Ryan, and Ola Hermanson for reviewing the manuscript, and Bjarti í Sumarhúsum for his hard work.


    Footnotes
 
Bogi Andersen and Michael G. Rosenfeld, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0648.

1 Supported by NIH Grants AR-044882 and AR-02080 and the Irving Weinstein Foundation. Back

2 Investigator with the Howard Hughes Medical Institute. Back


    References
 Top
 Abstract
 I. Introduction
 II. Structure and...
 III. Development of the...
 IV. Expression and Function...
 V. Relevance of POU...
 References
 

  1. Bodner M, Castrillo JL, Theill LE, Deerinck T, Ellisman M, Karin M 1988 The pituitary-specific transcription factor GHF-1 is a homeobox-containing protein. Cell 55:505–518[CrossRef][Medline]
  2. Ingraham HA, Chen RP, Mangalam HJ, Elsholtz HP, Flynn SE, Lin CR, Simmons DM, Swanson L, Rosenfeld MG 1988 A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell 55:519–529[CrossRef][Medline]
  3. Sturm RA, Das G, Herr W 1988 The ubiquitous octamer-binding protein Oct-1 contains a POU domain with a homeo box subdomain. Genes Dev 2:1582–1599[Abstract/Free Full Text]
  4. Muller MM, Ruppert S, Schaffner W, Matthias P 1988 A cloned octamer transcription factor stimulates transcription from lymphoid-specific promoters in non-B cells. Nature 336:544–551[CrossRef][Medline]
  5. Ko HS, Fast P, McBride W, Staudt LM 1988 A human protein specific for the immunoglobulin octamer DNA motif contains a functional homeobox domain. Cell 55:135–144[CrossRef][Medline]
  6. Scheidereit C, Cromlish JA, Gerster T, Kawakami K, Balmaceda CG, Currie RA, Roeder RG 1988 A human lymphoid-specific transcription factor that activates immunoglobulin genes is a homoeobox protein. Nature 336:551–557[CrossRef][Medline]
  7. Clerc RG, Corcoran LM, LeBowitz JH, Baltimore D, Sharp PA 1988 The B-cell-specific Oct-2 protein contains POU box- and homeo box-type domains. Genes Dev 2:1570–1581[Abstract/Free Full Text]
  8. Finney M, Ruvkun G 1990 The unc-86 gene product couples cell lineage and cell identity in C. elegans. Cell 63:895–905[CrossRef][Medline]
  9. Herr W, Sturm RA, Clerc RG, Corcoran LM, Baltimore D, Sharp PA, Ingraham HA, Rosenfeld MG, Finney M, Ruvkun G, Horvitz HR 1988 The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. Genes Dev 2:1513–1516[Free Full Text]
  10. Hsieh CL, Sturm R, Herr W, Francke U 1990 The gene for the ubiquitous octamer-binding protein Oct-1 is on human chromosome 1, region cen-q32, and near Ly-22 and Ltw-4 on mouse chromosome 1. Genomics 6:666–672[CrossRef][Medline]
  11. Siracusa LD, Rosner MH, Vigano MA, Gilbert DJ, Staudt LM, Copeland NG, Jenkins NA 1991 Chromosomal location of the octamer transcription factors, Otf-1, Otf- 2, and Otf-3, defines multiple Otf-3-related sequences dispersed in the mouse genome. Genomics 10:313–326[CrossRef][Medline]
  12. Yeom YI, Fuhrmann G, Ovitt CE, Brehm A, Ohbo K, Gross M, Hubner K, Scholer HR 1996 Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 122:881–894[Abstract]
  13. Sturm RA, Cassady JL, Das G, Romo A, Evans GA 1993 Chromosomal structure and expression of the human OTF1 locus encoding the Oct-1 protein. Genomics 16:333–341[CrossRef][Medline]
  14. Sturm RA, Eyre HJ, Baker E, Sutherland GR 1995 The human OTF1 locus which overlaps the CD3Z gene is located at 1q22– >q23. Cytogenet Cell Genet 68:231–232[Medline]
  15. Rohdewohld H, Gruss P 1992 The gene for the POU domain transcription factor Oct-6 maps to the distal end of mouse chromosome 4. Mamm Genome 3:119–121[CrossRef][Medline]
  16. Scholer HR, Dressler GR, Balling R, Rohdewohld H, Gruss P 1990 Oct-4: a germline-specific transcription factor mapping to the mouse t- complex. EMBO J 9:2185–2195[Medline]
  17. Takeda J, Seino S, Bell GI 1992 Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues. Nucleic Acids Res 20:4613–4620[Abstract/Free Full Text]
  18. Sumiyama K, Washio-Watanabe K, Ono T, Yoshida MC, Hayakawa T, Ueda S 1998 Human class III POU genes, POU3F1 and POU3F3, map to chromosomes 1p34.1 and 3p14.2. Mamm Genome 9:180–181[CrossRef][Medline]
  19. Xia YR, Andersen B, Mehrabian M, Diep AT, Warden CH, Mohandas T, McEvilly RJ, Rosenfeld MG, Lusis AJ 1993 Chromosomal organization of mammalian POU domain factors. Genomics 18:126–130[CrossRef][Medline]
  20. Burglin TR, Finney M, Coulson A, Ruvkun G 1989 Caenorhabditis elegans has scores of homoeobox-containing genes. Nature 341:239–243[CrossRef][Medline]
  21. Billin AN, Cockerill KA, Poole SJ 1991 Isolation of a family of Drosophila POU domain genes expressed in early development. Mech Dev 34:75–84[CrossRef][Medline]
  22. Johnson WA, Hirsh J 1990 Binding of a Drosophila POU-domain protein to a sequence element regulating gene expression in specific dopaminergic neurons. Nature 343:467–470[CrossRef][Medline]
  23. Thali M, Muller MM, DeLorenzi M, Matthias P, Bienz M 1988 Drosophila homoeotic genes encode transcriptional activators similar to mammalian OTF-2 [published erratum appears in Nature 1989 Jan 19;337(6204):290]. Nature 336:598–601[CrossRef][Medline]
  24. Agarwal VR, Sato SM 1991 XLPOU 1 and XLPOU 2, two novel POU domain genes expressed in the dorsoanterior region of Xenopus embryos. Dev Biol 147:363–373[CrossRef][Medline]
  25. Johansen T, Moens U, Holm T, Fjose A, Krauss S 1993 Zebrafish pou[c]: a divergent POU family gene ubiquitously expressed during embryogenesis. Nucleic Acids Res 21:475–483[Abstract/Free Full Text]
  26. Spaniol P, Bornmann C, Hauptmann G, Gerster T 1996 Class III POU genes of zebrafish are predominantly expressed in the central nervous system. Nucleic Acids Res 24:4874–4881[Abstract/Free Full Text]
  27. Li S, Crenshaw III EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG 1990 Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 347:528–533[CrossRef][Medline]
  28. Clark ME, Mellon PL 1995 The POU homeodomain transcription factor Oct-1 is essential for activity of the gonadotropin-releasing hormone neuron-specific enhancer. Mol Cell Biol 15:6169–6177[Abstract]
  29. Eraly SA, Nelson SB, Huang KM, Mellon PL 1998 Oct-1 binds promoter elements required for transcription of the GnRH gene. Mol Endocrinol 12:469–481[Abstract/Free Full Text]
  30. Hahm SH, Eiden LE 1998 Five discrete cis-active domains direct cell type-specific transcription of the vasoactive intestinal peptide (VIP) gene. J Biol Chem 273:17086–17094[Abstract/Free Full Text]
  31. Ojeda SR, Hill J, Hill DF, Costa ME, Tapia V, Cornea A, Ma YJ 1999 The Oct-2 POU domain gene in the neuroendocrine brain: a transcriptional regulator of mammalian puberty. Endocrinology 140:3774–3789[Abstract/Free Full Text]
  32. Yukawa K, Yasui T, Yamamoto A, Shiku H, Kishimoto T, Kikutani H 1993 Epoc-1: a POU-domain gene expressed in murine epidermal basal cells and thymic stromal cells. Gene 133:163–169[CrossRef][Medline]
  33. Goldsborough AS, Healy LE, Copeland NG, Gilbert DJ, Jenkins NA, Willison KR, Ashworth A 1993 Cloning, chromosomal localization and expression pattern of the POU domain gene Oct-11. Nucleic Acids Res 21:127–134[Abstract/Free Full Text]
  34. Andersen B, Schonemann MD, Flynn SE, Pearse RVd Singh H, Rosenfeld MG 1993 Skn-1a and Skn-1i: two functionally distinct Oct-2-related factors expressed in epidermis [published erratum appears in Science 1993 Dec 3;262(5139):1499]. Science 260:78–82[Abstract/Free Full Text]
  35. Andersen B, Weinberg WC, Rennekampff O, McEvilly RJ, Bermingham Jr JR, Hooshmand F, Vasilyev V, Hansbrough JF, Pittelkow MR, Yuspa SH, Rosenfeld MG 1997 Functions of the POU domain genes Skn-1a/i and Tst-1/Oct-6/SCIP in epidermal differentiation. Genes Dev 11:1873–1884[Abstract/Free Full Text]
  36. Hara Y, Rovescalli AC, Kim Y, Nirenberg M 1992 Structure and evolution of four POU domain genes expressed in mouse brain. Proc Natl Acad Sci USA 89:3280–3284[Abstract/Free Full Text]
  37. Nakai S, Kawano H, Yudate T, Nishi M, Kuno J, Nagata A, Jishage K, Hamada H, Fujii H, Kawamura K, Shiba K, Noda T 1995 The POU domain transcription factor Brn-2 is required for the determination of specific neuronal lineages in the hypothalamus of the mouse. Genes Dev 9:3109–3121[Abstract/Free Full Text]
  38. Schonemann MD, Ryan AK, McEvilly RJ, SM OC, Arias CA, Kalla KA, Li P, Sawchenko PE, Rosenfeld MG 1995 Development and survival of the endocrine hypothalamus and posterior pituitary gland requires the neuronal POU domain factor Brn-2. Genes Dev 9:3122–3135[Abstract/Free Full Text]
  39. Lillycrop KA, Budrahan VS, Lakin ND, Terrenghi G, Wood JN, Polak JM, Latchman DS 1992 A novel POU family transcription factor is closely related to Brn-3 but has a distinct expression pattern in neuronal cells. Nucleic Acids Res 20:5093–5096[Abstract/Free Full Text]
  40. Collum RG, Fisher PE, Datta M, Mellis S, Thiele C, Huebner K, Croce CM, Israel MA, Theil T, Moroy T, DePinho R, Alt FW 1992 A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system. Nucleic Acids Res 20:4919–4925[Abstract/Free Full Text]
  41. Ninkina NN, Stevens GE, Wood JN, Richardson WD 1993 A novel Brn3-like POU transcription factor expressed in subsets of rat sensory and spinal cord neurons. Nucleic Acids Res 21:3175–3182[Abstract/Free Full Text]
  42. Xiang M, Zhou L, Peng YW, Eddy RL, Shows TB, Nathans J 1993 Brn-3b: a POU domain gene expressed in a subset of retinal ganglion cells. Neuron 11:689–701[CrossRef][Medline]
  43. Turner EE, Jenne KJ, Rosenfeld MG 1994 Brn-3.2: a Brn-3-related transcription factor with distinctive central nervous system expression and regulation by retinoic acid. Neuron 12:205–218[CrossRef][Medline]
  44. Gan L, Xiang M, Zhou L, Wagner DS, Klein WH, Nathans J 1996 POU domain factor Brn-3b is required for the development of a large set of retinal ganglion cells. Proc Natl Acad Sci USA 93:3920–3925[Abstract/Free Full Text]
  45. Xiang M, Gan L, Zhou L, Klein WH, Nathans J 1996 Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling. Proc Natl Acad Sci USA 93:11950–11955[Abstract/Free Full Text]
  46. Xiang M, Gan L, Li D, Chen ZY, Zhou L, O Malley BW J, Klein W, Nathans J 1997 Essential role of POU-domain factor Brn-3c in auditory and vestibular hair cell development. Proc Natl Acad Sci USA 94:9445–9450[Abstract/Free Full Text]
  47. Erkman L, McEvilly RJ, Luo L, Ryan AK, Hooshmand F, O’Connell SM, Keithley EM, Rapaport DH, Ryan AF, Rosenfeld MG 1996 Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature 381:603–606[CrossRef][Medline]
  48. McEvilly RJ, Erkman L, Luo L, Sawchenko PE, Ryan AF, Rosenfeld MG 1996 Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons. Nature 384:574–577[CrossRef][Medline]
  49. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A 1998 Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379–391[CrossRef][Medline]
  50. Josephson R, Muller T, Pickel J, Okabe S, Reynolds K, Turner PA, Zimmer A, McKay RD 1998 POU transcription factors control expression of CNS stem cell-specific genes. Development 125:3087–3100[Abstract]
  51. Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H 1990 A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 60:461–472[CrossRef][Medline]
  52. Rosner MH, De Santo RJ, Arnheiter H, Staudt LM 1991 Oct-3 is a maternal factor required for the first mouse embryonic division [retracted by Rosner M, De Santo RJ, Arnheiter H, Staudt LM. In: Cell 1992 May 29;69(5):724]. Cell 64:1103–1110[CrossRef][Medline]
  53. Scholer HR, Ruppert S, Suzuki N, Chowdhury K, Gruss P 1990 New type of POU domain in germ line-specific protein Oct-4. Nature 344:435–439[CrossRef][Medline]
  54. Andersen B, Pearse II RV, Schlegel PN, Cichon Z, Schonemann MD, Bardin CW, Rosenfeld MG 1993 Sperm 1: a POU-domain gene transiently expressed immediately before meiosis I in the male germ cell. Proc Natl Acad Sci USA 90:11084–11088[Abstract/Free Full Text]
  55. Pearse II RV, Drolet DW, Kalla KA, Hooshmand F, Bermingham Jr JR, Rosenfeld MG 1997 Reduced fertility in mice deficient for the POU protein sperm-1. Proc Natl Acad Sci USA 94:7555–7560[Abstract/Free Full Text]
  56. Andersen B, Schonemann MD, Pearse II RV, Jenne K, Sugarman J, Rosenfeld MG 1993 Brn-5 is a divergent POU domain factor highly expressed in layer IV of the neocortex. J Biol Chem 268:23390–23398[Abstract/Free Full Text]
  57. Okamoto K, Wakamiya M, Noji S, Koyama E, Taniguchi S, Takemura R, Copeland NG, Gilbert DJ, Jenkins NA, Muramatsu M, Hamada H 1993 A novel class of murine POU gene predominantly expressed in central nervous system. J Biol Chem 268:7449–7457[Abstract/Free Full Text]
  58. Messier H, Brickner H, Gaikwad J, Fotedar A 1993 A novel POU domain protein which binds to the T-cell receptor {beta} enhancer. Mol Cell Biol 13:5450–5460[Abstract/Free Full Text]
  59. Zhou H, Yoshioka T, Nathans J 1996 Retina-derived POU-domain factor-1: a complex POU-domain gene implicated in the development of retinal ganglion and amacrine cells. J Neurosci 16:2261–2274[Abstract/Free Full Text]
  60. Baumruker T, Sturm R, Herr W 1988 OBP100 binds remarkably degenerate octamer motifs through specific interactions with flanking sequences. Genes Dev 2:1400–1413[Abstract/Free Full Text]
  61. Bendall AJ, Sturm RA, Danoy PA, Molloy PL 1993 Broad binding-site specificity and affinity properties of octamer 1 and brain octamer-binding proteins. Eur J Biochem 217:799–811[Medline]
  62. Cleary MA, Herr W 1995 Mechanisms for flexibility in DNA sequence recognition and VP16-induced complex formation by the Oct-1 POU domain. Mol Cell Biol 15:2090–2100[Abstract]
  63. Li P, He X, Gerrero MR, Mok M, Aggarwal A, Rosenfeld MG 1993 Spacing and orientation of bipartite DNA-binding motifs as potential functional determinants for POU domain factors. Genes Dev 7:2483–2496[Abstract/Free Full Text]
  64. Verrijzer CP, Kal AJ, van der Vliet PC 1990 The oct-1 homeo domain contacts only part of the octamer sequence and full oct-1 DNA-binding activity requires the POU-specific domain. Genes Dev 4:1964–1974[Abstract/Free Full Text]
  65. Verrijzer CP, Alkema MJ, van Weperen WW, Van Leeuwen HC, Strating MJ, van der Vliet PC 1992 The DNA binding specificity of the bipartite POU domain and its subdomains. EMBO J 11:4993–5003[Medline]
  66. Klemm JD, Rould MA, Aurora R, Herr W, Pabo CO 1994 Crystal structure of the Oct-1 POU domain bound to an octamer site: DNA recognition with tethered DNA-binding modules. Cell 77:21–32[CrossRef][Medline]
  67. van Leeuwen HC, Strating MJ, Rensen M, de Laat W, van der Vliet PC 1997 Linker length and composition influence the flexibility of Oct-1 DNA binding. EMBO J 16:2043–2053[CrossRef][Medline]
  68. McCormick A, Brady H, Theill LE, Karin M 1990 Regulation of the pituitary-specific homeobox gene GHF1 by cell-autonomous and environmental cues. Nature 345:829–832[CrossRef][Medline]
  69. Chen RP, Ingraham HA, Treacy MN, Albert VR, Wilson L, Rosenfeld MG 1990 Autoregulation of pit-1 gene expression mediated by two cis-active promoter elements. Nature 346:583–586[CrossRef][Medline]
  70. Rhodes SJ, Chen R, DiMattia GE, Scully KM, Kalla KA, Lin SC, Yu VC, Rosenfeld MG 1993 A tissue-specific enhancer confers Pit-1-dependent morphogen inducibility and autoregulation on the pit-1 gene. Genes Dev 7:913–932[Abstract/Free Full Text]
  71. Steinfelder HJ, Hauser P, Nakayama Y, Radovick S, McClaskey JH, Taylor T, Weintraub BD, Wondisford FE 1991 Thyrotropin-releasing hormone regulation of human TSHB expression: role of a pituitary-specific transcription factor (Pit-1/GHF-1) and potential interaction with a thyroid hormone-inhibitory element. Proc Natl Acad Sci USA 88:3130–3134[Abstract/Free Full Text]
  72. Lin SC, Li S, Drolet DW, Rosenfeld MG 1994 Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1dependent origins of the thyrotrope. Development 120:515–522[Abstract]
  73. Gordon DF, Haugen BR, Sarapura VD, Nelson AR, Wood WM, Ridgway EC 1993 Analysis of Pit-1 in regulating mouse TSH {beta} promoter activity in thyrotropes. Mol Cell Endocrinol 96:75–84[CrossRef][Medline]
  74. Iguchi G, Okimura Y, Takahashi T, Mizuno I, Fumoto M, Takahashi Y, Kaji H, Abe H, Chihara K 1999 Cloning and characterization of the 5'-flanking region of the human growth hormone-releasing hormone receptor gene. J Biol Chem 274:12108–12114[Abstract/Free Full Text]
  75. Miller TL, Godfrey PA, Dealmeida VI, Mayo KE 1999 The rat growth hormone-releasing hormone receptor gene: structure, regulation, and generation of receptor isoforms with different signaling properties. Endocrinology 140:4152–4165[Abstract/Free Full Text]
  76. Baumeister H, Wegner M, Richter D, Meyerhof W 2000 Dual regulation of somatostatin receptor subtype 1 gene expression by pit-1 in anterior pituitary GH3 cells. Mol Endocrinol 14:255–271[Abstract/Free Full Text]
  77. Baumeister H, Meyerhof W 1998 Involvement of a Pit-1 binding site in the regulation of the rat somatostatin receptor 1 gene expression. Ann NY Acad Sci 865:390–392[CrossRef][Medline]
  78. Matre V, Hovring PI, Orstavik S, Frengen E, Rian E, Velickovic Z, Murray-McIntosh RP, Gautvik KM 1999 Structural and functional organization of the gene encoding the human thyrotropin-releasing hormone receptor. J Neurochem 72:40–50[CrossRef][Medline]
  79. Elsholtz HP, Albert VR, Treacy MN, Rosenfeld MG 1990 A two-base change in a POU factor-binding site switches pituitary-specific to lymphoid-specific gene expression. Genes Dev 4:43–51[Abstract/Free Full Text]
  80. Ingraham HA, Flynn SE, Voss JW, Albert VR, Kapiloff MS, Wilson L, Rosenfeld MG 1990 The POU-specific domain of Pit-1 is essential for sequence-specific, high affinity DNA binding and DNA-dependent Pit-1-Pit-1 interactions. Cell 61:1021–1033[CrossRef][Medline]
  81. Voss JW, Wilson L, Rhodes SJ, Rosenfeld MG 1993 An alternative Pit-1 RNA splicing product reveals modular binding and nonmodular transcriptional activities of the POU-specific domain. Mol Endocrinol 7:1551–1560[Abstract/Free Full Text]
  82. Voss JW, Wilson L, Rosenfeld MG 1991 POU-domain proteins Pit-1 and Oct-1 interact to form a heteromeric complex and can cooperate to induce expression of the prolactin promoter. Genes Dev 5:1309–1320[Abstract/Free Full Text]
  83. Poellinger L, Roeder RG 1989 Octamer transcription factors 1 and 2 each bind to two different functional elements in the immunoglobulin heavy-chain promoter. Mol Cell Biol 9:747–756[Abstract/Free Full Text]
  84. Murphy S, Yoon JB, Gerster T, Roeder RG 1992 Oct-1 and Oct-2 potentiate functional interactions of a transcription factor with the proximal sequence element of small nuclear RNA genes. Mol Cell Biol 12:3247–3261[Abstract/Free Full Text]
  85. Tanaka M, Grossniklaus U, Herr W, Hernandez N 1988 Activation of the U2 snRNA promoter by the octamer motif defines a new class of RNA polymerase II enhancer elements [published erratum appears in Genes Dev 1989 Apr;3(4):584]. Genes Dev 2:1764–1778[Abstract/Free Full Text]
  86. La Bella F, Heintz N 1991 Histone gene transcription factor binding in extracts of normal human cells. Mol Cell Biol 11:5825–5831[Abstract/Free Full Text]
  87. apRhys CM, Ciufo DM, O’Neill EA, Kelly TJ, Hayward GS 1989 Overlapping octamer and TAATGARAT motifs in the VF65response elements in herpes simplex virus immediate-early promoters represent independent binding sites for cellular nuclear factor III. J Virol 63:2798–2812[Abstract/Free Full Text]
  88. Sturm R, Baumruker T, Franza Jr BR, Herr W 1987 A 100-kD HeLa cell octamer binding protein (OBP100) interacts differently with two separate octamer-related sequences within the SV40 enhancer. Genes Dev 1:1147–1160[Abstract/Free Full Text]
  89. Walker S, Hayes S, O’Hare P 1994 Site-specific conformational alteration of the Oct-1 POU domain-DNA complex as the basis for differential recognition by Vmw65 (VP16). Cell 79:841–852[CrossRef][Medline]
  90. Cleary MA, Pendergrast PS, Herr W 1997 Structural flexibility in transcription complex formation revealed by protein-DNA photocrosslinking. Proc Natl Acad Sci USA 94:8450–8455[Abstract/Free Full Text]
  91. Poellinger L, Yoza BK, Roeder RG 1989 Functional cooperativity between protein molecules bound at two distinct sequence elements of the immunoglobulin heavy-chain promoter. Nature 337:573–576[CrossRef][Medline]
  92. LeBowitz JH, Clerc RG, Brenowitz M, Sharp PA 1989 The Oct-2 protein binds cooperatively to adjacent octamer sites. Genes Dev 3:1625–1638[Abstract/Free Full Text]
  93. Kemler I, Schreiber E, Muller MM, Matthias P, Schaffner W 1989 Octamer transcription factors bind to two different sequence motifs of the immunoglobulin heavy chain promoter. EMBO J 8:2001–2008[Medline]
  94. Thomas MA, Mordvinov VA, Sanderson CJ 1999 The activity of the human interleukin-5 conserved lymphokine element 0 is regulated by octamer factors in human cells. Eur J Biochem 265:300–307[Medline]
  95. Mordvinov VA, Schwenger GT, Fournier R, De Boer ML, Peroni SE, Singh AD, Karlen S, Holland JW, Sanderson CJ 1999 Binding of YY1 and Oct1 to a novel element that downregulates expression of IL-5 in human T cells. J Allergy Clin Immunol 103:1125–1135[CrossRef][Medline]
  96. Andersen B, Hariri A, Pittelkow MR, Rosenfeld MG 1997 Characterization of Skn-1a/i POU domain factors and linkage to papillomavirus gene expression. J Biol Chem 272:15905–15913[Abstract/Free Full Text]
  97. Suzuki N, Rohdewohld H, Neuman T, Gruss P, Scholer HR 1990 Oct-6: a POU transcription factor expressed in embryonal stem cells and in the developing brain. EMBO J 9:3723–3732[Medline]
  98. Meijer D, Graus A, Kraay R, Langeveld A, Mulder MP, Grosveld G 1990 The octamer binding factor Oct6: cDNA cloning and expression in early embryonic cells. Nucleic Acids Res 18:7357–7365[Abstract/Free Full Text]
  99. He X, Gerrero R, Simmons DM, Park RE, Lin CJ, Swanson LW, Rosenfeld MG 1991 Tst-1, a member of the POU domain gene family, binds the promoter of the gene encoding the cell surface adhesion molecule Po. Mol Cell Biol 11:1739–1744[Abstract/Free Full Text]
  100. Wierman ME, Xiong X, Kepa JK, Spaulding AJ, Jacobsen BM, Fang Z, Nilaver G, Ojeda SR 1997 Repression of gonadotropin-releasing hormone promoter activity by the POU homeodomain transcription factor SCIP/Oct-6/Tst-1: a regulatory mechanism of phenotype expression? Mol Cell Biol 17:1652–1665[Abstract]
  101. Wegner M, Drolet DW, Rosenfeld MG 1993 Regulation of JC virus by the POU-domain transcription factor Tst-1: implications for progressive multifocal leukoencephalopathy. Proc Natl Acad Sci USA 90:4743–4747[Abstract/Free Full Text]
  102. Schreiber E, Tobler A, Malipiero U, Schaffner W, Fontana A 1993 cDna cloning of human N-Oct3, a nervous-system specific Pou domain transcription factor binding to the octamer Dna motif. Nucleic Acids Res 21:253–258[Abstract/Free Full Text]
  103. Rhee JM, Gruber CA, Brodie TB, Trieu M, Turner EE 1998 Highly cooperative homodimerization is a conserved property of neural POU proteins. J Biol Chem 273:34196–34205[Abstract/Free Full Text]
  104. Raynal JF, Dugast C, Le Van Thai A, Weber MJ 1998 Winged helix hepatocyte nuclear factor 3 and POU-domain protein brn-2/N- oct-3 bind overlapping sites on the neuronal promoter of human aromatic L-amino acid decarboxylase gene. Brain Res Mol Brain Res 56:227–237[Medline]
  105. Malik KF, Kim J, Hartman AL, Kim P, Young WS, 3rd 1996 Binding preferences of the POU domain protein Brain-4: implications for autoregulation. Brain Res Mol Brain Res 38:209–221[Medline]
  106. Okazawa H, Imafuku I, Minowa MT, Kanazawa I, Hamada H, Mouradian MM 1996 Regulation of striatal D1A dopamine receptor gene transcription by Brn- 4. Proc Natl Acad Sci USA 93:11933–11938[Abstract/Free Full Text]
  107. Hussain MA, Lee J, Miller CP, Habener JF 1997 POU domain transcription factor brain 4 confers pancreatic {alpha}-cell-specific expression of the proglucagon gene through interaction with a novel proximal promoter G1 element. Mol Cell Biol 17:7186–7194[Abstract]
  108. Ben-Shushan E, Thompson JR, Gudas LJ, Bergman Y 1998 Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site. Mol Cell Biol 18:1866–1878[Abstract/Free Full Text]
  109. Ambrosetti DC, Basilico C, Dailey L 1997 Synergistic activation of the fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein interactions facilitated by a specific spatial arrangement of factor binding sites. Mol Cell Biol 17:6321–6329[Abstract]
  110. Scholer HR, Balling R, Hatzopoulos AK, Suzuki N, Gruss P 1989 Octamer binding proteins confer transcriptional activity in early mouse embryogenesis. EMBO J 8:2551–2557[Medline]
  111. Botquin V, Hess H, Fuhrmann G, Anastassiadis C, Gross MK, Vriend G, Scholer HR 1998 New POU dimer configuration mediates antagonistic control of an osteopontin preimplantation enhancer by Oct-4 and Sox-2. Genes Dev 12:2073–2090[Abstract/Free Full Text]
  112. Nishimoto M, Fukushima A, Okuda A, Muramatsu M 1999 The gene for the embryonic stem cell coactivator UTF1 carries a regulatory element which selectively interacts with a complex composed of Oct-3/4 and Sox-2. Mol Cell Biol 19:5453–5465[Abstract/Free Full Text]
  113. Assa-Munt N, Mortishire-Smith RJ, Aurora R, Herr W, Wright PE 1993 The solution structure of the Oct-1 POU-specific domain reveals a striking similarity to the bacteriophage {lambda} repressor DNA-binding domain. Cell 73:193–205[CrossRef][Medline]
  114. Cox M, Dekker N, Boelens R, Verrijzer CP, van der Vliet PC, Kaptein R 1993 NMR studies of the POU-specific DNA-binding domain of Oct-1: sequential 1H and 15N assignments and secondary structure. Biochemistry 32:6032–6040[CrossRef][Medline]
  115. Dekker N, Cox M, Boelens R, Verrijzer CP, van der Vliet PC, Kaptein R 1993 Solution structure of the POU-specific DNA-binding domain of Oct-1. Nature 362:852–855[CrossRef][Medline]
  116. Sivaraja M, Botfield MC, Mueller M, Jancso A, Weiss MA 1994 Solution structure of a POU-specific homeodomain: 3D-NMR studies of human B-cell transcription factor Oct-2. Biochemistry 33:9845–9855[CrossRef][Medline]
  117. Jacobson EM, Li P, Leon-del-Rio A, Rosenfeld MG, Aggarwal AK 1997 Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility. Genes Dev 11:198–212[Abstract/Free Full Text]
  118. Fraenkel E, Rould MA, Chambers KA, Pabo CO 1998 Engrailed homeodomain-DNA complex at 2.2 A resolution: a detailed view of the interface and comparison with other engrailed structures. J Mol Biol 284:351–361[CrossRef][Medline]
  119. Fraenkel E, Pabo CO 1998 Comparison of X-ray and NMR structures for the Antennapedia homeodomain-DNA complex. Nat Struct Biol 5:692–697[Medline]
  120. Kissinger CR, Liu BS, Martin-Blanco E, Kornberg TB, Pabo CO 1990 Crystal structure of an engrailed homeodomain-DNA complex at 2.8 A resolution: a framework for understanding homeodomain-DNA interactions. Cell 63:579–590[CrossRef][Medline]
  121. Klemm JD, Pabo CO 1996 Oct-1 POU domain-DNA interactions: cooperative binding of isolated subdomains and effects of covalent linkage. Genes Dev 10:27–36[Abstract/Free Full Text]
  122. van Leeuwen HC, Rensen M, van der Vliet PC 1997 The Oct-1 POU homeodomain stabilizes the adenovirus preinitiation complex via a direct interaction with the priming protein and is displaced when the replication fork passes. J Biol Chem 272:3398–3405[Abstract/Free Full Text]
  123. Aurora R, Herr W 1992 Segments of the POU domain influence one another’s DNA-binding specificity. Mol Cell Biol 12:455–467[Abstract/Free Full Text]
  124. Sauter P, Matthias P 1998 Coactivator OBF-1 makes selective contacts with both the POU-specific domain and the POU homeodomain and acts as a molecular clamp on DNA. Mol Cell Biol 18:7397–7409[Abstract/Free Full Text]
  125. Segil N, Roberts SB, Heintz N 1991 Mitotic phosphorylation of the Oct-1 homeodomain and regulation of Oct-1 DNA binding activity. Science 254:1814–1816[Abstract/Free Full Text]
  126. Kapiloff MS, Farkash Y, Wegner M, Rosenfeld MG 1991 Variable effects of phosphorylation of Pit-1 dictated by the DNA response elements. Science 253:786–789[Abstract/Free Full Text]
  127. Okimura Y, Howard PW, Maurer RA 1994 Pit-1 binding sites mediate transcriptional responses to cyclic adenosine 3',5'-monophosphate through a mechanism that does not require inducible phosphorylation of Pit-1. Mol Endocrinol 8:1559–1565[Abstract/Free Full Text]
  128. Steinfelder HJ, Radovick S, Wondisford FE 1992 Hormonal regulation of the thyrotropin beta-subunit gene by phosphorylation of the pituitary-specific transcription factor Pit-1. Proc Natl Acad Sci USA 89:5942–5945[Abstract/Free Full Text]
  129. Kasibhatla S, Tailor P, Bonefoy-Berard N, Mustelin T, Altman A, Fotedar A 1999 Jun kinase phosphorylates and regulates the DNA binding activity of an octamer binding protein, T-cell factor {beta}1. Mol Cell Biol 19:2021–2031[Abstract/Free Full Text]
  130. Perissi V, Dasen JS, Kurokawa R, Wang Z, Korzus E, Rose DW, Glass CK, Rosenfeld MG 1999 Factor-specific modulation of CREB-binding protein acetyltransferase activity. Proc Natl Acad Sci USA 96:3652–3657[Abstract/Free Full Text]
  131. Herr W, Cleary MA 1995 The POU domain: versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain. Genes Dev 9:1679–1693[Free Full Text]
  132. Verrijzer CP, van Oosterhout JA, van der Vliet PC 1992 The Oct-1 POU domain mediates interactions between Oct-1 and other POU proteins. Mol Cell Biol 12:542–551[Abstract/Free Full Text]
  133. Day RN 1998 Visualization of Pit-1 transcription factor interactions in the living cell nucleus by fluorescence resonance energy transfer microscopy. Mol Endocrinol 12:1410–1419[Abstract/Free Full Text]
  134. Chang W, Zhou W, Theill LE, Baxter JD, Schaufele F 1996 An activation function in Pit-1 required selectively for synergistic transcription. J Biol Chem 271:17733–17738[Abstract/Free Full Text]
  135. Palomino T, Sanchez-Pacheco A, Pena P, Aranda A 1998 A direct protein-protein interaction is involved in the cooperation between thyroid hormone and retinoic acid receptors and the transcription factor GHF-1. FASEB J 12:1201–1209[Abstract/Free Full Text]
  136. Schaufele F, West BL, Baxter JD 1992 Synergistic activation of the rat growth hormone promoter by Pit-1 and the thyroid hormone receptor. Mol Endocrinol 6:656–665[Abstract/Free Full Text]
  137. Day RN, Koike S, Sakai M, Muramatsu M, Maurer RA 1990 Both Pit-1 and the estrogen receptor are required for estrogen responsiveness of the rat prolactin gene. Mol Endocrinol 4:1964–1971[Abstract/Free Full Text]
  138. Kakizawa T, Miyamoto T, Ichikawa K, Kaneko A, Suzuki S, Hara M, Nagasawa T, Takeda T, Mori J, Kumagai M, Hashizume K 1999 Functional interaction between Oct-1 and retinoid X receptor. J Biol Chem 274:19103–19108[Abstract/Free Full Text]
  139. Simmons DM, Voss JW, Ingraham HA, Holloway JM, Broide RS, Rosenfeld MG, Swanson LW 1990 Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev 4:695–711[Abstract/Free Full Text]
  140. Ying C, Lin DH, Sarkar DK, Chen TT 1999 Interaction between estrogen receptor and Pit-1 protein is influenced by estrogen in pituitary cells. J Steroid Biochem Mol Biol 68:145–152[CrossRef][Medline]
  141. Castillo AI, Jimenez-Lara AM, Tolon RM, Aranda A 1999 Synergistic activation of the prolactin promoter by vitamin D receptor and GHF-1: role of the coactivators, CREB-binding protein and steroid hormone receptor coactivator-1 (SRC-1). Mol Endocrinol 13:1141–1154[Abstract/Free Full Text]
  142. Nalda AM, Martial JA, Muller M 1997 The glucocorticoid receptor inhibits the human prolactin gene expression by interference with Pit-1 activity. Mol Cell Endocrinol 134:129–137[CrossRef][Medline]
  143. Szeto DP, Ryan AK, O’Connell SM, Rosenfeld MG 1996 P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proc Natl Acad Sci USA 93:7706–7710[Abstract/Free Full Text]
  144. Tremblay JJ, Lanctot C, Drouin J 1998 The pan-pituitary activator of transcription, Ptx1 (pituitary homeobox 1), acts in synergy with SF-1 and Pit1 and is an upstream regulator of the Lim-homeodomain gene Lim3/Lhx3. Mol Endocrinol 12:428–441[Abstract/Free Full Text]
  145. Szeto DP, Rodriguez-Esteban C, Ryan AK, O’Connell SM, Liu F, Kioussi C, Gleiberman AS, Izpisua-Belmonte JC, Rosenfeld MG 1999 Role of the bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev 13:484–494[Abstract/Free Full Text]
  146. Amendt BA, Sutherland LB, Russo AF 1999 Multifunctional role of the Pitx2 homeodomain protein C-terminal tail. Mol Cell Biol 19:7001–7010[Abstract/Free Full Text]
  147. Bach I, Rhodes SJ, Pearse II RV, Heinzel T, Gloss B, Scully KM, Sawchenko PE, Rosenfeld MG 1995 P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc Natl Acad Sci USA 92:2720–2724[Abstract/Free Full Text]
  148. Bradford AP, Wasylyk C, Wasylyk B, Gutierrez-Hartmann A 1997 Interaction of Ets-1 and the POU-homeodomain protein GHF-1/Pit-1 reconstitutes pituitary-specific gene expression. Mol Cell Biol 17:1065–1074[Abstract]
  149. Bradford AP, Brodsky KS, Diamond SE, Kuhn LC, Liu Y, Gutierrez-Hartmann A 2000 The pit-1 homeodomain and {beta}-domain interact with ets-1 and modulate synergistic activation of the rat prolactin promoter. J Biol Chem 275:3100–3106[Abstract/Free Full Text]
  150. Gordon DF, Lewis SR, Haugen BR, James RA, McDermott MT, Wood WM, Ridgway EC 1997 Pit-1 and GATA-2 interact and functionally cooperate to activate the thyrotropin {beta}-subunit promoter. J Biol Chem 272:24339–24347[Abstract/Free Full Text]
  151. Dasen JS, O’Connell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, Hooshmand F, Aggarwal AK, Rosenfeld MG 1999 Reciprocal interactions of Pit1 and GATA2 mediate signaling gradientinduced determination of pituitary cell types. Cell 97:587–598[CrossRef][Medline]
  152. Zanger K, Cohen LE, Hashimoto K, Radovick S, Wondisford FE 1999 A novel mechanism for cyclic adenosine 3',5'-monophosphate regulation of gene expression by CREB-binding protein. Mol Endocrinol 13:268–275[Abstract/Free Full Text]
  153. Xu L, Lavinsky RM, Dasen JS, Flynn SE, McInerney EM, Mullen TM, Heinzel T, Szeto D, Korzus E, Kurokawa R, Aggarwal AK, Rose DW, Glass CK, Rosenfeld MG 1998 Signal-specific co-activator domain requirements for Pit-1 activation. Nature 395:301–306[CrossRef][Medline]
  154. Vigano MA, Staudt LM 1996 Transcriptional activation by Oct-3: evidence for a specific role of the POU-specific domain in mediating functional interaction with Oct-1. Nucleic Acids Res 24:2112–2118[Abstract/Free Full Text]
  155. Liu M, Freedman LP 1994 Transcriptional synergism between the vitamin D3 receptor and other nonreceptor transcription factors. Mol Endocrinol 8:1593–1604[Abstract/Free Full Text]
  156. Prefontaine GG, Lemieux ME, Giffin W, Schild-Poulter C, Pope L, LaCasse E, Walker P, Hache RJ 1998 Recruitment of octamer transcription factors to DNA by glucocorticoid receptor. Mol Cell Biol 18:3416–3430[Abstract/Free Full Text]
  157. Wang JM, Prefontaine GG, Lemieux ME, Pope L, Akimenko MA, Hache RJ 1999 Developmental effects of ectopic expression of the glucocorticoid receptor DNA binding domain are alleviated by an amino acid substitution that interferes with homeodomain binding. Mol Cell Biol 19:7106–7122[Abstract/Free Full Text]
  158. Chandran UR, Warren BS, Baumann CT, Hager GL, DeFranco DB 1999 The glucocorticoid receptor is tethered to DNA-bound Oct-1 at the mouse gonadotropin-releasing hormone distal negative glucocorticoid response element. J Biol Chem 274:2372–2378[Abstract/Free Full Text]
  159. Bruggemeier U, Kalff M, Franke S, Scheidereit C, Beato M 1991 Ubiquitous transcription factor OTF-1 mediates induction of the MMTV promoter through synergistic interaction with hormone receptors. Cell 64:565–572[CrossRef][Medline]
  160. Prefontaine GG, Walther R, Giffin W, Lemieux ME, Pope L, Hache RJ 1999 Selective binding of steroid hormone receptors to octamer transcription factors determines transcriptional synergism at the mouse mammary tumor virus promoter. J Biol Chem 274:26713–26719[Abstract/Free Full Text]
  161. Truss M, Bartsch J, Schelbert A, Hache RJ, Beato M 1995 Hormone induces binding of receptors and transcription factors to a rearranged nucleosome on the MMTV promoter in vivo. EMBO J 14:1737–1751[Medline]
  162. Pina B, Bruggemeier U, Beato M 1990 Nucleosome positioning modulates accessibility of regulatory proteins to the mouse mammary tumor virus promoter. Cell 60:719–731[CrossRef][Medline]
  163. Wieland S, Dobbeling U, Rusconi S 1991 Interference and synergism of glucocorticoid receptor and octamer factors. EMBO J 10:2513–2521[Medline]
  164. Kutoh E, Stromstedt PE, Poellinger L 1992 Functional interference between the ubiquitous and constitutive octamer transcription factor 1 (OTF-1) and the glucocorticoid receptor by direct protein-protein interaction involving the homeo subdomain of OTF- 1. Mol Cell Biol 12:4960–4969[Abstract/Free Full Text]
  165. Song CS, Jung MH, Kim SC, Hassan T, Roy AK, Chatterjee B 1998 Tissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoter. J Biol Chem 273:21856–21866[Abstract/Free Full Text]
  166. Strom AC, Forsberg M, Lillhager P, Westin G 1996 The transcription factors Sp1 and Oct-1 interact physically to regulate human U2 snRNA gene expression. Nucleic Acids Res 24:1981–1986[Abstract/Free Full Text]
  167. Janson L, Pettersson U 1990 Cooperative interactions between transcription factors Sp1 and OTF-1. Proc Natl Acad Sci USA 87:4732–4736[Abstract/Free Full Text]
  168. Ullman KS, Flanagan WM, Edwards CA, Crabtree GR 1991 Activation of early gene expression in T lymphocytes by Oct-1 and an inducible protein, OAP40. Science 254:558–562[Abstract/Free Full Text]
  169. Pfeuffer I, Klein-Hessling S, Heinfling A, Chuvpilo S, Escher C, Brabletz T, Hentsch B, Schwarzenbach H, Matthias P, Serfling E 1994 Octamer factors exert a dual effect on the IL-2 and IL-4 promoters. J Immunol 153:5572–5585[Abstract]
  170. de Grazia U, Felli MP, Vacca A, Farina AR, Maroder M, Cappabianca L, Meco D, Farina M, Screpanti I, Frati L, Gulino A 1994 Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, Oct-2, and retinoic acid receptor. J Exp Med 180:1485–1497[Abstract/Free Full Text]
  171. Hatada EN, Chen-Kiang S, Scheidereit C 2000 Interaction and functional interference of C/EBP{beta} with octamer factors in immunoglobulin gene transcription. Eur J Immunol 30:174–184[CrossRef][Medline]
  172. O’Connor M, Bernard HU 1995 Oct-1 activates the epithelialspecific enhancer of human papillomavirus type 16 via a synergistic interaction with NFI at a conserved composite regulatory element. Virology 207:77–88[CrossRef][Medline]
  173. Oberdick J, Smeyne RJ, Mann JR, Zackson S, Morgan JI 1990 A promoter that drives transgene expression in cerebellar Purkinje and retinal bipolar neurons. Science 248:223–226[Abstract/Free Full Text]
  174. Lakich MM, Diagana TT, North DL, Whalen RG 1998 MEF-2 and Oct-1 bind to two homologous promoter sequence elements and participate in the expression of a skeletal muscle-specific gene. J Biol Chem 273:15217–15226[Abstract/Free Full Text]
  175. Zwilling S, Konig H, Wirth T 1995 High mobility group protein 2 functionally interacts with the POU domains of octamer transcription factors. EMBO J 14:1198–1208[Medline]
  176. Abdulkadir SA, Krishna S, Thanos D, Maniatis T, Strominger JL, Ono SJ 1995 Functional roles of the transcription factor Oct-2A and the high mobility group protein I/Y in HLA-DRA gene expression. J Exp Med 182:487–500[Abstract/Free Full Text]
  177. Abdulkadir SA, Casolaro V, Tai AK, Thanos D, Ono SJ 1998 High mobility group I/Y protein functions as a specific cofactor for Oct-2A: mapping of interaction domains. J Leukoc Biol 64:681–691[Abstract]
  178. Gstaiger M, Knoepfel L, Georgiev O, Schaffner W, Hovens CM 1995 A B-cell coactivator of octamer-binding transcription factors. Nature 373:360–362[CrossRef][Medline]
  179. Luo Y, Roeder RG 1995 Cloning, functional characterization, and mechanism of action of the B-cell-specific transcriptional coactivator OCA-B. Mol Cell Biol 15:4115–4124[Abstract]
  180. Luo Y, Ge H, Stevens S, Xiao H, Roeder RG 1998 Coactivation by OCA-B: definition of critical regions and synergism with general cofactors. Mol Cell Biol 18:3803–3810[Abstract/Free Full Text]
  181. Luo Y, Fujii H, Gerster T, Roeder RG 1992 A novel B cell-derived coactivator potentiates the activation of immunoglobulin promoters by octamer-binding transcription factors. Cell 71:231–241[CrossRef][Medline]
  182. Schubart DB, Rolink A, Kosco-Vilbois MH, Botteri F, Matthias P 1996 B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation. Nature 383:538–542[CrossRef][Medline]
  183. Strubin M, Newell JW, Matthias P 1995 OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins. Cell 80:497–506[CrossRef][Medline]
  184. Babb R, Cleary MA, Herr W 1997 OCA-B is a functional analog of VP16 but targets a separate surface of the Oct-1 POU domain [published erratum appears in Mol Cell Biol 1998 Apr;18(4):2430]. Mol Cell Biol 17:7295–7305[Abstract]
  185. Matthias P 1998 Lymphoid-specific transcription mediated by the conserved octamer site: who is doing what? Semin Immunol 10:155–163[CrossRef][Medline]
  186. Chang JF, Phillips K, Lundback T, Gstaiger M, Ladbury JE, Luisi B 1999 Oct-1 POU and octamer DNA co-operate to recognise the Bob-1 transcription co-activator via induced folding. J Mol Biol 288:941–952[CrossRef][Medline]
  187. Chasman D, Cepek K, Sharp PA, Pabo CO 1999 Crystal structure of an OCA-B peptide bound to an Oct-1 POU domain/octamer DNA complex: specific recognition of a protein-DNA interface. Genes Dev 13:2650–2657[Abstract/Free Full Text]
  188. Kristie TM, LeBowitz JH, Sharp PA 1989 The octamer-binding proteins form multi-protein–DNA complexes with the HSV {alpha} TIF regulatory protein. EMBO J 8:4229–4238[Medline]
  189. Kristie TM, Sharp PA 1990 Interactions of the Oct-1 POU subdomains with specific DNA sequences and with the HSV {alpha}-trans-activator protein. Genes Dev 4:2383–2396[Abstract/Free Full Text]
  190. Stern S, Tanaka M, Herr W 1989 The Oct-1 homoeodomain directs formation of a multiprotein-DNA complex with the HSV transactivator VP16. Nature 341:624–630[CrossRef][Medline]
  191. Stern S, Herr W 1991 The herpes simplex virus trans-activator VP16 recognizes the Oct-1 homeo domain: evidence for a homeo domain recognition subdomain. Genes Dev 5:2555–2566[Abstract/Free Full Text]
  192. Gerster T, Roeder RG 1988 A herpesvirus trans-activating protein interacts with transcription factor OTF-1 and other cellular proteins. Proc Natl Acad Sci USA 85:6347–6351[Abstract/Free Full Text]
  193. La Boissiere S, Hughes T, O’Hare P 1999 HCF-dependent nuclear import of VP16. EMBO J 18:480–489[CrossRef][Medline]
  194. Wilson AC, LaMarco K, Peterson MG, Herr W 1993 The VP16 accessory protein HCF is a family of polypeptides processed from a large precursor protein. Cell 74:115–125[CrossRef][Medline]
  195. Wilson AC, Parrish JE, Massa HF, Nelson DL, Trask BJ, Herr W 1995 The gene encoding the VP16-accessory protein HCF (HCFC1) resides in human Xq28 and is highly expressed in fetal tissues and the adult kidney. Genomics 25:462–468[CrossRef][Medline]
  196. Katan M, Haigh A, Verrijzer CP, van der Vliet PC, O’Hare P 1990 Characterization of a cellular factor which interacts functionally with Oct-1 in the assembly of a multicomponent transcription complex. Nucleic Acids Res 18:6871–6880[Abstract/Free Full Text]
  197. Xiao P, Capone JP 1990 A cellular factor binds to the herpes simplex virus type 1 transactivator Vmw65 and is required for Vmw65-dependent protein-DNA complex assembly with Oct-1. Mol Cell Biol 10:4974–4977[Abstract/Free Full Text]
  198. Cleary MA, Stern S, Tanaka M, Herr W 1993 Differential positive control by Oct-1 and Oct-2: activation of a transcriptionally silent motif through Oct-1 and VP16 corecruitment. Genes Dev 7:72–83[Abstract/Free Full Text]
  199. Lai JS, Cleary MA, Herr W 1992 A single amino acid exchange transfers VP16-induced positive control from the Oct-1 to the Oct-2 homeo domain [published erratum appears in Genes Dev 1992 Dec;6(12B):2663]. Genes Dev 6:2058–2065[Abstract/Free Full Text]
  200. Pomerantz JL, Kristie TM, Sharp PA 1992 Recognition of the surface of a homeo domain protein. Genes Dev 6:2047–2057[Abstract/Free Full Text]
  201. Yoon JB, Murphy S, Bai L, Wang Z, Roeder RG 1995 Proximal sequence element-binding transcription factor (PTF) is a multisubunit complex required for transcription of both RNA polymerase II- and RNA polymerase III-dependent small nuclear RNA genes. Mol Cell Biol 15:2019–2027[Abstract]
  202. Henry RW, Sadowski CL, Kobayashi R, Hernandez N 1995 A TBP-TAF complex required for transcription of human snRNA genes by RNA polymerase II and III. Nature 374:653–656[CrossRef][Medline]
  203. Wong MW, Henry RW, Ma B, Kobayashi R, Klages N, Matthias P, Strubin M, Hernandez N 1998 The large subunit of basal transcription factor SNAPc is a Myb domain protein that interacts with Oct-1. Mol Cell Biol 18:368–377[Abstract/Free Full Text]
  204. Ford E, Hernandez N 1997 Characterization of a trimeric complex containing Oct-1, SNAPc, and DNA. J Biol Chem 272:16048–16055[Abstract/Free Full Text]
  205. Mittal V, Cleary MA, Herr W, Hernandez N 1996 The Oct-1 POU-specific domain can stimulate small nuclear RNA gene transcription by stabilizing the basal transcription complex SNAPc. Mol Cell Biol 16:1955–1965[Abstract]
  206. Mittal V, Ma B, Hernandez N 1999 SNAP(c): a core promoter factor with a built-in DNA-binding damper that is deactivated by the Oct-1 POU domain. Genes Dev 13:1807–1821[Abstract/Free Full Text]
  207. Zwilling S, Annweiler A, Wirth T 1994 The POU domains of the Oct1 and Oct2 transcription factors mediate specific interaction with TBP. Nucleic Acids Res 22:1655–1662[Abstract/Free Full Text]
  208. Arnosti DN, Merino A, Reinberg D, Schaffner W 1993 Oct-2 facilitates functional preinitiation complex assembly and is continuously required at the promoter for multiple rounds of transcription. EMBO J 12:157–166[Medline]
  209. Nakshatri H, Nakshatri P, Currie RA 1995 Interaction of Oct-1 with TFIIB. Implications for a novel response elicited through the proximal octamer site of the lipoprotein lipase promoter. J Biol Chem 270:19613–19623[Abstract/Free Full Text]
  210. Inamoto S, Segil N, Pan ZQ, Kimura M, Roeder RG 1997 The cyclin-dependent kinase-activating kinase (CAK) assembly factor, MAT1, targets and enhances CAK activity on the POU domains of octamer transcription factors. J Biol Chem 272:29852–29858[Abstract/Free Full Text]
  211. de Jong RN, van der Vliet PC 1999 Mechanism of DNA replication in eukaryotic cells: cellular host factors stimulating adenovirus DNA replication. Gene 236:1–12[CrossRef][Medline]
  212. Verrijzer CP, Kal AJ, Van der Vliet PC 1990 The DNA binding domain (POU domain) of transcription factor oct-1 suffices for stimulation of DNA replication. EMBO J 9:1883–1888[Medline]
  213. Botting CH, Hay RT 1999 Characterisation of the adenovirus preterminal protein and its interaction with the POU homeodomain of NFIII (Oct-1). Nucleic Acids Res 27:2799–2805[Abstract/Free Full Text]
  214. Coenjaerts FE, van Oosterhout JA, van der Vliet PC 1994 The Oct-1 POU domain stimulates adenovirus DNA replication by a direct interaction between the viral precursor terminal protein-DNA polymerase complex and the POU homeodomain. EMBO J 13:5401–5409[Medline]
  215. Verrijzer CP, Strating M, Mul YM, van der Vliet PC 1992 POU domain transcription factors from different subclasses stimulate adenovirus DNA replication. Nucleic Acids Res 20:6369–6375[Abstract/Free Full Text]
  216. Malik KF, Jaffe H, Brady J, Young III WS 1997 The class III POU factor Brn-4 interacts with other class III POU factors and the heterogeneous nuclear ribonucleoprotein U. Brain Res Mol Brain Res 45:99–107[Medline]
  217. Leger H, Sock E, Renner K, Grummt F, Wegner M 1995 Functional interaction between the POU domain protein Tst-1/Oct-6 and the high-mobility-group protein HMG-I/Y. Mol Cell Biol 15:3738–3747[Abstract]
  218. Zwilling S, Dieckmann A, Pfisterer P, Angel P, Wirth T 1997 Inducible expression and phosphorylation of coactivator BOB.1/OBF.1 in T cells. Science 277:221–225[Abstract/Free Full Text]
  219. Kuhlbrodt K, Herbarth B, Sock E, Enderich J, Hermans-Borgmeyer I, Wegner M 1998 Cooperative function of POU proteins and SOX proteins in glial cells. J Biol Chem 273:16050–16057[Abstract/Free Full Text]
  220. Kuhlbrodt K, Herbarth B, Sock E, Hermans-Borgmeyer I, Wegner M 1998 Sox10, a novel transcriptional modulator in glial cells. J Neurosci 18:237–250[Abstract/Free Full Text]
  221. Renner K, Leger H, Wegner M 1994 The POU domain protein Tst-1 and papovaviral large tumor antigen function synergistically to stimulate glia-specific gene expression of JC virus. Proc Natl Acad Sci USA 91:6433–6437[Abstract/Free Full Text]
  222. Renner K, Sock E, Gerber JK, Wegner M 1996 T antigen of human papovavirus JC stimulates transcription of the POU domain factor Tst-1/Oct6/SCIP. DNA Cell Biol 15:1057–1062[Medline]
  223. Sock E, Enderich J, Wegner M 1999 The J domain of papovaviral large tumor antigen is required for synergistic interaction with the POU-domain protein Tst-1/Oct6/SCIP. Mol Cell Biol 19:2455–2464[Abstract/Free Full Text]
  224. Yuan H, Corbi N, Basilico C, Dailey L 1995 Developmentalspecific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev 9:2635–2645[Abstract/Free Full Text]
  225. Scholer HR, Ciesiolka T, Gruss P 1991 A nexus between Oct-4 and E1A: implications for gene regulation in embryonic stem cells. Cell 66:291–304[CrossRef][Medline]
  226. Brehm A, Ohbo K, Zwerschke W, Botquin V, Jansen-Durr P, Scholer HR 1999 Synergism with germ line transcription factor Oct-4: viral oncoproteins share the ability to mimic a stem cell-specific activity. Mol Cell Biol 19:2635–2643[Abstract/Free Full Text]
  227. Tanaka M, Herr W 1990 Differential transcriptional activation by Oct-1 and Oct-2: interdependent activation domains induce Oct-2 phosphorylation. Cell 60:375–386[CrossRef][Medline]
  228. Tanaka M, Lai JS, Herr W 1992 Promoter-selective activation domains in Oct-1 and Oct-2 direct differential activation of an snRNA and mRNA promoter. Cell 68:755–767[CrossRef][Medline]
  229. Tanaka M, Clouston WM, Herr W 1994 The Oct-2 glutamine-rich and proline-rich activation domains can synergize with each other or duplicates of themselves to activate transcription. Mol Cell Biol 14:6046–6055[Abstract/Free Full Text]
  230. Muller-Immergluck MM, Schaffner W, Matthias P 1990 Transcription factor Oct-2A contains functionally redundant activating domains and works selectively from a promoter but not from a remote enhancer position in non-lymphoid (HeLa) cells. EMBO J 9:1625–1634[Medline]
  231. Gerster T, Balmaceda CG, Roeder RG 1990 The cell type-specific octamer transcription factor OTF-2 has two domains required for the activation of transcription. EMBO J 9:1635–1643[Medline]
  232. Tanaka M, Herr W 1994 Reconstitution of transcriptional activation domains by reiteration of short peptide segments reveals the modular organization of a glutamine- rich activation domain. Mol Cell Biol 14:6056–6067[Abstract/Free Full Text]
  233. Brehm A, Ohbo K, Scholer H 1997 The carboxy-terminal transactivation domain of Oct-4 acquires cell specificity through the POU domain. Mol Cell Biol 17:154–162[Abstract]
  234. Holloway JM, Szeto DP, Scully KM, Glass CK, Rosenfeld MG 1995 Pit-1 binding to specific DNA sites as a monomer or dimer determines gene-specific use of a tyrosine-dependent synergy domain. Genes Dev 9:1992–2006[Abstract/Free Full Text]
  235. Caskey CT, Pizzuti A, Fu YH, Fenwick Jr RG, Nelson DL 1992 Triplet repeat mutations in human disease. Science 256:784–789[Abstract/Free Full Text]
  236. Waragai M, Lammers CH, Takeuchi S, Imafuku I, Udagawa Y, Kanazawa I, Kawabata M, Mouradian MM, Okazawa H 1999 PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival. Hum Mol Genet 8:977–987[Abstract/Free Full Text]
  237. Friedl EM, Matthias P 1995 Transcriptional activation and repression, two properties of the lymphoid-specific transcription factor Oct-2a. Eur J Biochem 234:308–316[Medline]
  238. Friedl EM, Matthias P 1996 Mapping of the transcriptional repression domain of the lymphoid- specific transcription factor oct-2A. J Biol Chem 271:13927–13930[Abstract/Free Full Text]
  239. Gay RD, Dawson SJ, Latchman DS 1997 The different inhibitory domains of the Oct-2 transcription factor have distinct functional activities. FEBS Lett 416:135–138[CrossRef][Medline]
  240. Lillycrop KA, Dawson SJ, Estridge JK, Gerster T, Matthias P, Latchman DS 1994 Repression of a herpes simplex virus immediate-early promoter by the Oct-2 transcription factor is dependent on an inhibitory region at the N terminus of the protein. Mol Cell Biol 14:7633–7642[Abstract/Free Full Text]
  241. Liu YZ, Dawson SJ, Gerster T, Friedl E, Pengue G, Matthias P, Lania L, Latchman DS 1996 The ability of the inhibitory domain of the POU family transcription factor Oct-2 to interfere with promoter activation by different classes of activation domains is dependent upon the nature of the basal promoter elements. J Biol Chem 271:20853–20860[Abstract/Free Full Text]
  242. Liu YZ, Lee IK, Locke I, Dawson SJ, Latchman DS 1998 Adjacent proline residues in the inhibitory domain of the Oct-2 transcription factor play distinct functional roles. Nucleic Acids Res 26:2464–2472[Abstract/Free Full Text]
  243. Berger SL 1999 Gene activation by histone and factor acetyltransferases. Curr Opin Cell Biol 11:336–341[CrossRef][Medline]
  244. Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA 2000 Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev 14:45–54[Abstract/Free Full Text]
  245. Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG 1997 A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387:43–48[CrossRef][Medline]
  246. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, Rosenfeld MG 1995 Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377:397–404[CrossRef][Medline]
  247. Laherty CD, Billin AN, Lavinsky RM, Yochum GS, Bush AC, Sun JM, Mullen TM, Davie JR, Rose DW, Glass CK, Rosenfeld MG, Ayer DE, Eisenman RN 1998 SAP30, a component of the mSin3 corepressor complex involved in N-CoR- mediated repression by specific transcription factors. Mol Cell 2:33–42[CrossRef][Medline]
  248. Kioussi C, Carriere C, Rosenfeld MG 1999 A model for the development of the hypothalamic-pituitary axis: transcribing the hypophysis. Mech Dev 81:23–35[CrossRef][Medline]
  249. Treier M, Rosenfeld MG 1996 The hypothalamic-pituitary axis: co-development of two organs. Curr Opin Cell Biol 8:833–843[CrossRef][Medline]
  250. Andersen B, Rosenfeld MG 1994 Pit-1 determines cell types during development of the anterior pituitary gland. A model for transcriptional regulation of cell phenotypes in mammalian organogenesis. J Biol Chem 269:29335–29338[Free Full Text]
  251. Osumi-Yamashita N, Ninomiya Y, Doi H, Eto K 1994 The contribution of both forebrain and midbrain crest cells to the mesenchyme in the frontonasal mass of mouse embryos. Dev Biol 164:409–419[CrossRef][Medline]
  252. Watanabe YG 1982 Effects of brain and mesenchyme upon the cytogenesis of rat adenohypophysis in vitro. I. Differentiation of adrenocorticotropes. Cell Tissue Res 227:257–266[CrossRef][Medline]
  253. Watanabe YG 1985 Effects of brain and mesenchyme upon the cytogenesis of rat adenohypophysis in vitro. II. Differentiation of LH cells. Cell Tissue Res 242:49–55[Medline]
  254. Gleiberman AS, Fedtsova NG, Rosenfeld MG 1999 Tissue interactions in the induction of anterior pituitary: role of the ventral diencephalon, mesenchyme, and notochord. Dev Biol 213:340–353[CrossRef][Medline]
  255. Fedtsova NG, Barabanov VM 1990 [The distribution of competence for adenohypophysis development in the ectoderm of chick embryos]. Ontogenez 21:254–260[Medline]
  256. Alvarez-Bolado G, Rosenfeld MG, Swanson LW 1995 Model of forebrain regionalization based on spatiotemporal patterns of POU-III homeobox gene expression, birthdates, and morphological features. J Comp Neurol 355:237–295[CrossRef][Medline]
  257. Schwanzel-Fukuda M, Pfaff DW 1989 Origin of luteinizing hormone-releasing hormone neurons. Nature 338:161–164[CrossRef][Medline]
  258. Japon MA, Rubinstein M, Low MJ 1994 In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J Histochem Cytochem 42:1117–1125[Abstract]
  259. Watanabe YG, Daikoku S 1979 An immunohistochemical study on the cytogenesis of adenohypophysial cells in fetal rats. Dev Biol 68:557–567[CrossRef][Medline]
  260. Lugo DI, Roberts JL, Pintar JE 1989 Analysis of proopiomelanocortin gene expression during prenatal development of the rat pituitary gland. Mol Endocrinol 3:1313–1324[Abstract/Free Full Text]
  261. Treier M, Gleiberman AS, SM OC, Szeto DP, McMahon JA, McMahon AP, Rosenfeld MG 1998 Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev 12:1691–1704[Abstract/Free Full Text]
  262. Takuma N, Sheng HZ, Furuta Y, Ward JM, Sharma K, Hogan BL, Pfaff SL, Westphal H, Kimura S, Mahon KA 1998 Formation of Rathke’s pouch requires dual induction from the diencephalon. Development 125:4835–4840[Abstract]
  263. Ericson J, Norlin S, Jessell TM, Edlund T 1998 Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development 125:1005–1015[Abstract]
  264. Theill LE, Castrillo JL, Wu D, Karin M 1989 Dissection of functional domains of the pituitary-specific transcription factor GHF-1. Nature 342:945–948[CrossRef][Medline]
  265. Konzak KE, Moore DD 1992 Functional isoforms of Pit-1 generated by alternative messenger RNA splicing. Mol Endocrinol 6:241–247[Abstract/Free Full Text]
  266. Morris AE, Kloss B, McChesney RE, Bancroft C, Chasin LA 1992 An alternatively spliced Pit-1 isoform altered in its ability to trans-activate. Nucleic Acids Res 20:1355–1361[Abstract/Free Full Text]
  267. Day RN, Day KH 1994 An alternatively spliced form of Pit-1 represses prolactin gene expression. Mol Endocrinol 8:374–381[Abstract/Free Full Text]
  268. Haugen BR, Wood WM, Gordon DF, Ridgway EC 1993 A thyrotrope-specific variant of Pit-1 transactivates the thyrotropin {beta} promoter. J Biol Chem 268:20818–20824[Abstract/Free Full Text]
  269. Theill LE, Hattori K, Lazzaro D, Castrillo JL, Karin M 1992 Differential splicing of the GHF1 primary transcript gives rise to two functionally distinct homeodomain proteins. EMBO J 11:2261–2269[Medline]
  270. Majumdar S, Irwin DM, Elsholtz HP 1996 Selective constraints on the activation domain of transcription factor Pit-1. Proc Natl Acad Sci USA 93:10256–10261[Abstract/Free Full Text]
  271. Diamond SE, Gutierrez-Hartmann A 1996 A 26-amino acid insertion domain defines a functional transcription switch motif in Pit-1{beta}. J Biol Chem 271:28925–28932[Abstract/Free Full Text]
  272. Haugen BR, Gordon DF, Nelson AR, Wood WM, Ridgway EC 1994 The combination of Pit-1 and Pit-1T have a synergistic stimulatory effect on the thyrotropin beta-subunit promoter but not the growth hormone or prolactin promoters. Mol Endocrinol 8:1574–1582[Abstract/Free Full Text]
  273. Gaddy-Kurten D, Vale WW 1995 Activin increases phosphorylation and decreases stability of the transcription factor Pit-1 in MtTW15 somatotrope cells. J Biol Chem 270:28733–28739[Abstract/Free Full Text]
  274. Dolle P, Castrillo JL, Theill LE, Deerinck T, Ellisman M, Karin M 1990 Expression of GHF-1 protein in mouse pituitaries correlates both temporally and spatially with the onset of growth hormone gene activity. Cell 60:809–820[CrossRef][Medline]
  275. Mangalam HJ, Albert VR, Ingraham HA, Kapiloff M, Wilson L, Nelson C, Elsholtz H, Rosenfeld MG 1989 A pituitary POU domain protein, Pit-1, activates both growth hormone and prolactin promoters transcriptionally. Genes Dev 3:946–958[Abstract/Free Full Text]
  276. Nelson C, Albert VR, Elsholtz HP, Lu LI, Rosenfeld MG 1988 Activation of cell-specific expression of rat growth hormone and prolactin genes by a common transcription factor. Science 239:1400–1405[Abstract/Free Full Text]
  277. Jones BK, Monks BR, Liebhaber SA, Cooke NE 1995 The human growth hormone gene is regulated by a multicomponent locus control region. Mol Cell Biol 15:7010–7021[Abstract]
  278. Bennani-Baiti IM, Asa SL, Song D, Iratni R, Liebhaber SA, Cooke NE 1998 DNase I-hypersensitive sites I and II of the human growth hormone locus control region are a major developmental activator of somatotrope gene expression. Proc Natl Acad Sci USA 95:10655–10660[Abstract/Free Full Text]
  279. Jin Y, Surabhi RM, Fresnoza A, Lytras A, Cattini PA 1999 A role for A/T-rich sequences and Pit-1/GHF-1 in a distal enhancer located in the human growth hormone locus control region with preferential pituitary activity in culture and transgenic mice. Mol Endocrinol 13:1249–1266[Abstract/Free Full Text]
  280. Shewchuk BM, Asa SL, Cooke NE, Liebhaber SA 1999 Pit-1 binding sites at the somatotrope-specific DNase I hypersensitive sites I, II of the human growth hormone locus control region are essential for in vivo hGH-N gene activation. J Biol Chem 274:35725–35733[Abstract/Free Full Text]
  281. Boulikas T 1992 Homeotic protein binding sites, origins of replication, and nuclear matrix anchorage sites share the ATTA and ATTTA motifs. J Cell Biochem 50:111–123[Medline]
  282. Mancini MG, Liu B, Sharp ZD, Mancini MA 1999 Subnuclear partitioning and functional regulation of the Pit-1 transcription factor. J Cell Biochem 72:322–338[CrossRef][Medline]
  283. Castrillo JL, Theill LE, Karin M 1991 Function of the homeodomain protein GHF1 in pituitary cell proliferation. Science 253:197–199[Abstract/Free Full Text]
  284. Gaiddon C, de Tapia M, Loeffler JP 1999 The tissue-specific transcription factor Pit-1/GHF-1 binds to the c-fos serum response element and activates c-fos transcription. Mol Endocrinol 13:742–751[Abstract/Free Full Text]
  285. Lin C, Lin SC, Chang CP, Rosenfeld MG 1992 Pit-1-dependent expression of the receptor for growth hormone releasing factor mediates pituitary cell growth. Nature 360:765–768[CrossRef][Medline]
  286. Petersenn S, Rasch AC, Heyens M, Schulte HM 1998 Structure and regulation of the human growth hormone-releasing hormone receptor gene. Mol Endocrinol 12:233–247[Abstract/Free Full Text]
  287. Korytko AI, Zeitler P, Cuttler L 1996 Developmental regulation of pituitary growth hormone-releasing hormone receptor gene expression in the rat. Endocrinology 137:1326–1331[Abstract]
  288. DiMattia GE, Rhodes SJ, Krones A, Carriere C, O’Connell S, Kalla K, Arias C, Sawchenko P, Rosenfeld MG 1997 The Pit-1 gene is regulated by distinct early and late pituitary-specific enhancers. Dev Biol 182:180–190[CrossRef][Medline]
  289. Andersen B, Pearse II RV, Jenne K, Sornson M, Lin SC, Bartke A, Rosenfeld MG 1995 The Ames dwarf gene is required for Pit-1 gene activation. Dev Biol 172:495–503[CrossRef][Medline]
  290. Crenshaw III EB, Kalla K, Simmons DM, Swanson LW, Rosenfeld MG 1989 Cell-specific expression of the prolactin gene in transgenic mice is controlled by synergistic interactions between promoter and enhancer elements. Genes Dev 3:959–972[Abstract/Free Full Text]
  291. Kim MK, Lesoon-Wood LA, Weintraub BD, Chung JH 1996 A soluble transcription factor, Oct-1, is also found in the insoluble nuclear matrix and possesses silencing activity in its alanine-rich domain. Mol Cell Biol 16:4366–4377[Abstract]
  292. Palomino T, Barettino D, Aranda A 1998 Role of GHF-1 in the regulation of the rat growth hormone gene promoter by thyroid hormone and retinoic acid receptors. J Biol Chem 273:27541–27547[Abstract/Free Full Text]
  293. Lipkin SM, Naar AM, Kalla KA, Sack RA, Rosenfeld MG 1993 Identification of a novel zinc finger protein binding a conserved element critical for Pit-1-dependent growth hormone gene expression. Genes Dev 7:1674–1687[Abstract/Free Full Text]
  294. Schaufele F 1996 CCAAT/enhancer-binding protein alpha activation of the rat growth hormone promoter in pituitary progenitor GHFT1–5 cells. J Biol Chem 271:21484–21489[Abstract/Free Full Text]
  295. Schaufele F 1999 Regulation of estrogen receptor activation of the prolactin enhancer/promoter by antagonistic activation function-2-interacting proteins. Mol Endocrinol 13:935–945[Abstract/Free Full Text]
  296. Chuang FM, West BL, Baxter JD, Schaufele F 1997 Activities in Pit-1 determine whether receptor interacting protein 140 activates or inhibits Pit-1/nuclear receptor transcriptional synergy. Mol Endocrinol 11:1332–1341[Abstract/Free Full Text]
  297. Bradford AP, Conrad KE, Wasylyk C, Wasylyk B, Gutierrez-Hartmann A 1995 Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary-specific gene expression: mapping of the essential c-Ets-1 domain. Mol Cell Biol 15:2849–2857[Abstract]
  298. Bradford AP, Conrad KE, Tran PH, Ostrowski MC, Gutierrez-Hartmann A 1996 GHF-1/Pit-1 functions as a cell-specific integrator of Ras signaling by targeting the Ras pathway to a composite Ets-1/GHF-1 response element. J Biol Chem 271:24639–24648[Abstract/Free Full Text]
  299. Howard PW, Maurer RA 1995 A composite Ets/Pit-1 binding site in the prolactin gene can mediate transcriptional responses to multiple signal transduction pathways. J Biol Chem 270:20930–20936[Abstract/Free Full Text]
  300. Day RN, Liu J, Sundmark V, Kawecki M, Berry D, Elsholtz HP 1998 Selective inhibition of prolactin gene transcription by the ETS-2 repressor factor. J Biol Chem 273:31909–31915[Abstract/Free Full Text]
  301. Kim MK, McClaskey JH, Bodenner DL, Weintraub BD 1993 An AP-1-like factor and the pituitary-specific factor Pit-1 are both necessary to mediate hormonal induction of human thyrotropin beta gene expression. J Biol Chem 268:23366–23375[Abstract/Free Full Text]
  302. Gutierrez-Hartmann A 1994 INSIGHT: Pit-1/GHF-1: a pituitary-specific transcription factor linking general signaling pathways to cell-specific gene expression. Mol Endocrinol 8:1447–1449[Free Full Text]
  303. Cohen LE, Hashimoto Y, Zanger K, Wondisford F, Radovick S 1999 CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression. J Clin Invest 104:1123–1130[Medline]
  304. McChesney R, Sealfon SC, Tsutsumi M, Dong KW, Roberts JL, Bancroft C 1991 Either isoform of the dopamine D2 receptor can mediate dopaminergic repression of the rat prolactin promoter. Mol Cell Endocrinol 79:R1–7
  305. Fischberg DJ, Chen XH, Bancroft C 1994 A Pit-1 phosphorylation mutant can mediate both basal and induced prolactin and growth hormone promoter activity. Mol Endocrinol 8:1566–1573[Abstract/Free Full Text]
  306. Diamond SE, Chiono M, Gutierrez-Hartmann A 1999 Reconstitution of the protein kinase A response of the rat prolactin promoter: differential effects of distinct Pit-1 isoforms and functional interaction with Oct-1. Mol Endocrinol 13:228–238[Abstract/Free Full Text]
  307. Yan GZ, Bancroft C 1991 Mediation by calcium of thyrotropin-releasing hormone action on the prolactin promoter via transcription factor pit-1. Mol Endocrinol 5:1488–1497[Abstract/Free Full Text]
  308. Yan GZ, Pan WT, Bancroft C 1991 Thyrotropin-releasing hormone action on the prolactin promoter is mediated by the POU protein pit-1. Mol Endocrinol 5:535–541[Abstract/Free Full Text]
  309. Kambe F, Tsukahara S, Kato T, Seo H 1993 The POU-domain protein Oct-1 is widely expressed in adult rat organs. Biochim Biophys Acta 1171:307–310[Medline]
  310. Matheos DD, Ruiz MT, Price GB, Zannis-Hadjopoulos M 1998 Oct-1 enhances the in vitro replication of a mammalian autonomously replicating DNA sequence. J Cell Biochem 68:309–327[CrossRef][Medline]
  311. Mul YM, Verrijzer CP, van der Vliet PC 1990 Transcription factors NFI and NFIII/oct-1 function independently, employing different mechanisms to enhance adenovirus DNA replication. J Virol 64:5510–5518[Abstract/Free Full Text]
  312. Lakin ND, Palmer R, Lillycrop KA, Howard MK, Burke LC, Thomas NS, Latchman DS 1995 Down regulation of the octamer binding protein Oct-1 during growth arrest and differentiation of a neuronal cell line. Brain Res Mol Brain Res 28:47–54[Medline]
  313. Hatzopoulos AK, Stoykova AS, Erselius JR, Goulding M, Neuman T, Gruss P 1990 Structure and expression of the mouse Oct2a and Oct2b, two differentially spliced products of the same gene. Development 109:349–362[Abstract]
  314. Eraly SA, Mellon PL 1995 Regulation of gonadotropin-releasing hormone transcription by protein kinase C is mediated by evolutionarily conserved promoter-proximal elements. Mol Endocrinol 9:848–859[Abstract/Free Full Text]
  315. Kepa JK, Jacobsen BM, Boen EA, Prendergast P, Edwards DP, Takimoto G, Wierman ME 1996 Direct binding of progesterone receptor to nonconsensus DNA sequences represses rat GnRH. Mol Cell Endocrinol 117:27–39[CrossRef][Medline]
  316. Belsham DD, Wetsel WC, Mellon PL 1996 NMDA and nitric oxide act through the cGMP signal transduction pathway to repress hypothalamic gonadotropin-releasing hormone gene expression. EMBO J 15:538–547[Medline]
  317. Belsham DD, Mellon PL 2000 Transcription factors Oct-1 and C/EBP{beta} (CCAAT/enhancer-binding protein-{beta}) are involved in the glutamate/nitric oxide/cyclic- guanosine 5'-monophosphatemediated repression of mediated repression of gonadotropinreleasing hormone gene expression. Mol Endocrinol 14:212–228[Abstract/Free Full Text]
  318. Liu XK, Abernethy DR, Andrawis NS 1998 Nitric oxide inhibits Oct-1 DNA binding activity in cultured vascular smooth muscle cells. Life Sci 62:739–749[CrossRef][Medline]
  319. Chandran UR, DeFranco DB 1999 Regulation of gonadotropin-releasing hormone gene transcription. Behav Brain Res 105:29–36[CrossRef][Medline]
  320. Chandran UR, Attardi B, Friedman R, Zheng Z, Roberts JL, DeFranco DB 1996 Glucocorticoid repression of the mouse gonadotropin-releasing hormone gene is mediated by promoter elements that are recognized by heteromeric complexes containing glucocorticoid receptor. J Biol Chem 271:20412–20420[Abstract/Free Full Text]
  321. Gozes I, Brenneman DE 1989 VIP: molecular biology and neurobiological function. Mol Neurobiol 3:201–236[Medline]
  322. Rostene WH 1984 Neurobiological and neuroendocrine functions of the vasoactive intestinal peptide (VIP). Prog Neurobiol 22:103–129[CrossRef][Medline]
  323. Lin HK, Penning TM 1995 Cloning, sequencing, and functional analysis of the 5'-flanking region of the rat 3 {alpha}-hydroxysteroid/dihydrodiol dehydrogenase gene. Cancer Res 55:4105–4113[Abstract/Free Full Text]
  324. Malone CS, Patrone L, Buchanan KL, Webb CF, Wall R 2000 An upstream oct-1- and oct-2-binding silencer governs B29 (Ig{beta}) gene expression. J Immunol 164:2550–2556[Abstract/Free Full Text]
  325. Imai S, Nishibayashi S, Takao K, Tomifuji M, Fujino T, Hasegawa M, Takano T 1997 Dissociation of Oct-1 from the nuclear peripheral structure induces the cellular aging-associated collagenase gene expression. Mol Biol Cell 8:2407–2419[Abstract/Free Full Text]
  326. van Wijnen AJ, Bidwell JP, Fey EG, Penman S, Lian JB, Stein JL, Stein GS 1993 Nuclear matrix association of multiple sequence-specific DNA binding activities related to SP-1, ATF, CCAAT, C/EBP, OCT-1, and AP-1. Biochemistry 32:8397–8402[CrossRef][Medline]
  327. Stoykova AS, Sterrer S, Erselius JR, Hatzopoulos AK, Gruss P 1992 Mini-Oct and Oct-2c: two novel, functionally diverse murine Oct-2 gene products are differentially expressed in the CNS. Neuron 8:541–558[CrossRef][Medline]
  328. He X, Treacy MN, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG 1989 Expression of a large family of POU-domain regulatory genes in mammalian brain development [published erratum appears in Nature 1989 Aug 24;340(6235):662]. Nature 340:35–41[CrossRef][Medline]
  329. Wirth T, Priess A, Annweiler A, Zwilling S, Oeler B 1991 Multiple Oct2 isoforms are generated by alternative splicing. Nucleic Acids Res 19:43–51[Abstract/Free Full Text]
  330. Lillycrop KA, Latchman DS 1992 Alternative splicing of the Oct-2 transcription factor RNA is differentially regulated in neuronal cells and B cells and results in protein isoforms with opposite effects on the activity of octamer/TAATGARAT-containing promoters. J Biol Chem 267:24960–24965[Abstract/Free Full Text]
  331. Corcoran LM, Karvelas M 1994 Oct-2 is required early in T cell-independent B cell activation for G1 progression and for proliferation [published erratum appears in Immunity 1995 Feb;2(2):following 203]. Immunity 1:635–645[CrossRef][Medline]
  332. Corcoran LM, Karvelas M, Nossal GJ, Ye ZS, Jacks T, Baltimore D 1993 Oct-2, although not required for early B-cell development, is critical for later B-cell maturation and for postnatal survival. Genes Dev 7:570–582[Abstract/Free Full Text]
  333. Ninkina NN, Buchman VL, Akopian AN, Lawson SN, Yamamoto M, Campbell E, Corcoran L, Wood JN 1995 Nerve growth factor-regulated properties of sensory neurones in Oct-2 null mutant mice. Brain Res Mol Brain Res 33:233–244[Medline]
  334. Mathis JM, Simmons DM, He X, Swanson LW, Rosenfeld MG 1992 Brain 4: a novel mammalian POU domain transcription factor exhibiting restricted brain-specific expression. EMBO J 11:2551–2561[Medline]
  335. Le Moine C, Young III WS 1992 RHS2, a POU domain-containing gene, and its expression in developing and adult rat. Proc Natl Acad Sci USA 89:3285–3289[Abstract/Free Full Text]
  336. Zwart R, Broos L, Grosveld G, Meijer D 1996 The restricted expression pattern of the POU factor Oct-6 during early development of the mouse nervous system. Mech Dev 54:185–194[CrossRef][Medline]
  337. Kovacs KJ, Sawchenko PE 1996 Sequence of stress-induced alterations in indices of synaptic and transcriptional activation in parvocellular neurosecretory neurons. J Neurosci 16:262–273[Abstract/Free Full Text]
  338. Mihailescu D, Kury P, Monard D 1999 An octamer-binding site is crucial for the activity of an enhancer active at the embryonic met-/mesencephalic junction. Mech Dev 84:55–67[CrossRef][Medline]
  339. Cui H, Bulleit RF 1998 Expression of the POU transcription factor Brn-5 is an early event in the terminal differentiation of CNS neurons. J Neurosci Res 52:625–632[CrossRef][Medline]
  340. Waller SJ, Ratty A, Burbach JP, Murphy D 1998 Transgenic and transcriptional studies on neurosecretory cell gene expression. Cell Mol Neurobiol 18:149–171[CrossRef][Medline]
  341. Ramkumar T, Adler S 1999 A requirement for the POU transcription factor, Brn-2, in corticotropin- releasing hormone expression in a neuronal cell line. Mol Endocrinol 13:1237–1248[Abstract/Free Full Text]
  342. Michaud JL, Rosenquist T, May NR, Fan CM 1998 Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1. Genes Dev 12:3264–3275[Abstract/Free Full Text]
  343. Minowa O, Ikeda K, Sugitani Y, Oshima T, Nakai S, Katori Y, Suzuki M, Furukawa M, Kawase T, Zheng Y, Ogura M, Asada Y, Watanabe K, Yamanaka H, Gotoh S, Nishi-Takeshima M, Sugimoto T, Kikuchi T, Takasaka T, Noda T 1999 Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness. Science 285:1408–1411[Abstract/Free Full Text]
  344. Phippard D, Lu L, Lee D, Saunders JC, Crenshaw III EB 1999 Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental defects in the inner ear. J Neurosci 19:5980–5989[Abstract/Free Full Text]
  345. Monuki ES, Weinmaster G, Kuhn R, Lemke G 1989 SCIP: a glial POU domain gene regulated by cyclic AMP. Neuron 3:783–793[CrossRef][Medline]
  346. Monuki ES, Kuhn R, Weinmaster G, Trapp BD, Lemke G 1990 Expression and activity of the POU transcription factor SCIP. Science 249:1300–1303[Abstract/Free Full Text]
  347. Jaegle M, Mandemakers W, Broos L, Zwart R, Karis A, Visser P, Grosveld F, Meijer D 1996 The POU factor Oct-6 and Schwann cell differentiation. Science 273:507–510[Abstract]
  348. Bermingham Jr JR, Scherer SS, O’Connor S, Arroyo E, Kalla KA, Powell FL, Rosenfeld MG 1996 Tst-1/Oct-6/SCIP regulates a unique step in peripheral myelination and is required for normal respiration. Genes Dev 10:1751–1762[Abstract/Free Full Text]
  349. Rosner MH, Vigano MA, Ozato K, Timmons PM, Poirier F, Rigby PW, Staudt LM 1990 A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature 345:686–692[CrossRef][Medline]
  350. Wey E, Lyons GE, Schafer BW 1994 A human POU domain gene, mPOU, is expressed in developing brain and specific adult tissues. Eur J Biochem 220:753–762[Medline]
  351. Bulleit RF, Cui H, Wang J, Lin X 1994 NMDA receptor activation in differentiating cerebellar cell cultures regulates the expression of a new POU gene, Cns-1. J Neurosci 14:1584–1595[Abstract]
  352. Cui H, Bulleit RF 1997 Expression of the POU transcription factor Brn-5 inhibits proliferation of NG108–15 cells. Biochem Biophys Res Commun 236:693–696[CrossRef][Medline]
  353. Parks JS, Brown MR, Hurley DL, Phelps CJ, Wajnrajch MP 1999 Heritable disorders of pituitary development. J Clin Endocrinol Metab 84:4362–4370[Abstract/Free Full Text]
  354. Cohen LE, Radovick S, Wondisford FE 1999 Transcription factors and hypopituitarism. Trends Endocrinol Metab 10:326–332[CrossRef][Medline]
  355. Pfaffle RW, Blankenstein O, Wuller S, Kentrup H 1999 Combined pituitary hormone deficiency: role of Pit-1 and Prop-1. Acta Paediatr Suppl 88:33–41[CrossRef]
  356. Radovick S, Cohen LE, Wondisford FE 1998 The molecular basis of hypopituitarism. Horm Res 49[Suppl 1]:30–36
  357. de Zegher F, Pernasetti F, Vanhole C, Devlieger H, Van den Berghe G, Martial JA 1995 The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency. J Clin Endocrinol Metab 80:3127–3130[Abstract]
  358. Pfaffle RW, DiMattia GE, Parks JS, Brown MR, Wit JM, Jansen M, Van der Nat H, Van den Brande JL, Rosenfeld MG, Ingraham HA 1992 Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 257:1118–1121[Abstract/Free Full Text]
  359. Pellegrini-Bouiller I, Belicar P, Barlier A, Gunz G, Charvet JP, Jaquet P, Brue T, Vialettes B, Enjalbert A 1996 A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 81:2790–2796[Abstract/Free Full Text]
  360. Pernasetti F, Milner RD, al Ashwal AA, de Zegher F, Chavez VM, Muller M, Martial JA 1998 Pro239Ser: a novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency. J Clin Endocrinol Metab 83:2079–2083[Abstract/Free Full Text]
  361. Brown MR, Parks JS, Adess ME, Rich BH, Rosenthal IM, Voss TC, VanderHeyden TC, Hurley DL 1998 Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene. Horm Res 49:98–102[CrossRef][Medline]
  362. Tatsumi K, Miyai K, Notomi T, Kaibe K, Amino N, Mizuno Y, Kohno H 1992 Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet 1:56–58[CrossRef][Medline]
  363. Ohta K, Nobukuni Y, Mitsubuchi H, Fujimoto S, Matsuo N, Inagaki H, Endo F, Matsuda I 1992 Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency. Biochem Biophys Res Commun 189:851–855[CrossRef][Medline]
  364. Irie Y, Tatsumi K, Ogawa M, Kamijo T, Preeyasombat C, Suprasongsin C, Amino N 1995 A novel E250X mutation of the PIT1 gene in a patient with combined pituitary hormone deficiency. Endocr J 42:351–354[Medline]
  365. Aarskog D, Eiken HG, Bjerknes R, Myking OL 1997 Pituitary dwarfism in the R271W Pit-1 gene mutation. Eur J Pediatr 156:829–834[CrossRef][Medline]
  366. Radovick S, Nations M, Du Y, Berg LA, Weintraub BD, Wondisford FE 1992 A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 257:1115–1118[Abstract/Free Full Text]
  367. Okamoto N, Wada Y, Ida S, Koga R, Ozono K, Chiyo H, Hayashi A, Tatsumi K 1994 Monoallelic expression of normal mRNA in the PIT1 mutation heterozygotes with normal phenotype and biallelic expression in the abnormal phenotype. Hum Mol Genet 3:1565–1568[Abstract/Free Full Text]
  368. Cohen LE, Wondisford FE, Salvatoni A, Maghnie M, Brucker-Davis F, Weintraub BD, Radovick S 1995 A "hot spot" in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates. J Clin Endocrinol Metab 80:679–684[Abstract]
  369. Holl RW, Pfaffle R, Kim C, Sorgo W, Teller WM, Heimann G 1997 Combined pituitary deficiencies of growth hormone, thyroid stimulating hormone and prolactin due to Pit-1 gene mutation: a case report. Eur J Pediatr 156:835–837[CrossRef][Medline]
  370. Fofanova OV, Takamura N, Kinoshita E, Yoshimoto M, Tsuji Y, Peterkova VA, Evgrafov OV, Dedov II, Goncharov NP, Yamashita S 1998 Rarity of PIT1 involvement in children from Russia with combined pituitary hormone deficiency. Am J Med Genet 77:360–365[CrossRef][Medline]
  371. Ward L, Chavez M, Huot C, Lecocq P, Collu R, Decarie JC, Martial JA, Van Vliet G 1998 Severe congenital hypopituitarism with low prolactin levels and age-dependent anterior pituitary hypoplasia: a clue to a PIT-1 mutation. J Pediatr 132:1036–1038[CrossRef][Medline]
  372. Cohen LE, Zanger K, Brue T, Wondisford FE, Radovick S 1999 Defective retinoic acid regulation of the Pit-1 gene enhancer: a novel mechanism of combined pituitary hormone deficiency. Mol Endocrinol 13:476–484[Abstract/Free Full Text]
  373. Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, SM OC, Gukovsky I, Carriere C, Ryan AK, Miller AP, Zuo L, Gleiberman AS, Andersen B, Beamer WG, Rosenfeld MG 1996 Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 384:327–333[CrossRef][Medline]
  374. Pernasetti F, Toledo SP, Vasilyev VV, Hayashida CY, Cogan JD, Ferrari C, Lourenco DM, Mellon PL 2000 Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301–302delAG) in the prophet of Pit-1 gene. J Clin Endocrinol Metab 85:390–397[Abstract/Free Full Text]
  375. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, Pembrey ME, Ropers HH, Cremers FP 1995 Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science 267:685–688[Abstract/Free Full Text]
  376. Nakamura S, Ohtsuru A, Takamura N, Kitange G, Tokunaga Y, Yasunaga A, Shibata S, Yamashita S 1999 Prop-1 gene expression in human pituitary tumors. J Clin Endocrinol Metab 84:2581–2584[Abstract/Free Full Text]
  377. Sanno N, Teramoto A, Sugiyama M, Matsuno A, Takumi I, Tahara S, Osamura RY 1998 Expression of Pit-1 mRNA and activin/inhibin subunits in clinically nonfunctioning pituitary adenomas. In situ hybridization and immunohistochemical analysis. Horm Res 50:11–17[CrossRef][Medline]
  378. Sanno N, Teramoto A, Matsuno A, Osamura RY 1996 Expression of human Pit-1 product in the human pituitary and pituitary adenomas. Immunohistochemical studies using an antibody against synthetic human Pit-1 product. Arch Pathol Lab Med 120:73–77[Medline]
  379. Sanno N, Teramoto A, Matsuno A, Itoh J, Takekoshi S, Osamura RY 1996 In situ hybridization analysis of Pit-1 mRNA and hormonal production in human pituitary adenomas. Acta Neuropathol (Berl) 91:263–268[CrossRef][Medline]
  380. Sanno N, Teramoto A, Matsuno A, Takekoshi S, Itoh J, Osamura RY 1996 Expression of Pit-1 and estrogen receptor messenger RNA in prolactin- producing pituitary adenomas. Mod Pathol 9:526–533[Medline]
  381. Yamada S, Takahashi M, Hara M, Hattori A, Sano T, Ozawa Y, Shishiba Y, Hirata K, Usui M 1996 Pit-1 gene expression in human pituitary adenomas using the reverse transcription polymerase chain reaction method. Clin Endocrinol (Oxf) 45:263–272[CrossRef][Medline]
  382. Pellegrini-Bouiller I, Morange-Ramos I, Barlier A, Gunz G, Enjalbert A, Jaquet P 1997 Pit-1 gene expression in human pituitary adenomas. Horm Res 47:251–258[Medline]
  383. Otsuka F, Tamiya T, Yamauchi T, Ogura T, Ohmoto T, Makino H 1999 Quantitative analysis of growth-related factors in human pituitary adenomas. Lowered insulin-like growth factor-I and its receptor mRNA in growth hormone-producing adenomas. Regul Pept 83:31–38[CrossRef][Medline]
  384. Hamada K, Nishi T, Kuratsu J, Ushio Y 1996 Expression and alternative splicing of Pit-1 messenger ribonucleic acid in pituitary adenomas. Neurosurgery 38:362–366[CrossRef][Medline]
  385. Pellegrini I, Barlier A, Gunz G, Figarella-Branger D, Enjalbert A, Grisoli F, Jaquet P 1994 Pit-1 gene expression in the human pituitary and pituitary adenomas. J Clin Endocrinol Metab 79:189–196[Abstract]
  386. Elsholtz HP, Lew AM, Albert PR, Sundmark VC 1991 Inhibitory control of prolactin and Pit-1 gene promoters by dopamine. Dual signaling pathways required for D2 receptor-regulated expression of the prolactin gene. J Biol Chem 266:22919–22925[Abstract/Free Full Text]
  387. Lew AM, Yao H, Elsholtz HP 1994 G(i) {alpha} 2- and G(o) {alpha}-mediated signaling in the Pit-1-dependent inhibition of the prolactin gene promoter. Control of transcription by dopamine D2 receptors. J Biol Chem 269:12007–12013[Abstract/Free Full Text]
  388. Asa SL, Kelly MA, Grandy DK, Low MJ 1999 Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice. Endocrinology 140:5348–5355[Abstract/Free Full Text]
  389. Barlier A, Pellegrini-Bouiller I, Caccavelli L, Gunz G, Morange-Ramos I, Jaquet P, Enjalbert A 1997 Abnormal transduction mechanisms in pituitary adenomas. Horm Res 47:227–234[Medline]
  390. Gaiddon C, Tian J, Loeffler JP, Bancroft C 1996 Constitutively active G(S) alpha-subunits stimulate Pit-1 promoter activity via a protein kinase A-mediated pathway acting through deoxyribonucleic acid binding sites both for Pit-1 and for adenosine 3',5'-monophosphate response element-binding protein. Endocrinology 137:1286–1291[Abstract]
  391. Gaiddon C, Mercken L, Bancroft C, Loeffler JP 1995 Transcriptional effects in GH3 cells of Gs alpha mutants associated with human pituitary tumors: stimulation of adenosine 3',5'-monophosphate response element-binding protein-mediated transcription and of prolactin and growth hormone promoter activity via protein kinase A. Endocrinology 136:4331–4338[Abstract]
  392. Barlier A, Pellegrini-Bouiller I, Gunz G, Zamora AJ, Jaquet P, Enjalbert A 1999 Impact of gsp oncogene on the expression of genes coding for Gs{alpha}, Pit-1, Gi2{alpha}, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity. J Clin Endocrinol Metab 84:2759–2765[Abstract/Free Full Text]
  393. Hermesz E, Mackem S, Mahon KA 1996 Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke’s pouch of the mouse embryo. Development 122:41–52[Abstract]
  394. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC 1998 Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19:125–133[CrossRef][Medline]
  395. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB 1999 The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12[Abstract]
  396. Lugaresi E, Tobler I, Gambetti P, Montagna P 1998 The pathophysiology of fatal familial insomnia. Brain Pathol 8:521–526[Medline]
  397. Stoving RK, Hangaard J, Hansen-Nord M, Hagen C 1999 A review of endocrine changes in anorexia nervosa. J Psychiatr Res 33:139–152[CrossRef][Medline]
  398. Lefevre C, Imagawa M, Dana S, Grindlay J, Bodner M, Karin M 1987 Tissue-specific expression of the human growth hormone gene is conferred in part by the binding of a specific trans-acting factor. EMBO J 6:971–981[Medline]
  399. Fadel BM, Boutet SC, Quertermous T 1999 Octamer-dependent in vivo expression of the endothelial cell-specific TIE2 gene. J Biol Chem 274:20376–20383[Abstract/Free Full Text]
  400. Bhat R, Weaver JA, Sterling KM, Bresnick E 1996 Nuclear transcription factor Oct-1 binds to the 5'-upstream region of CYP1A1 and negatively regulates its expression. Int J Biochem Cell Biol 28:217–227[CrossRef][Medline]
  401. Bingle CD, Gowan S 1996 Oct-1 interacts with conserved motifs in the human thyroid transcription factor 1 gene minimal promoter. Biochem J 319:669–674
  402. Celis L, Claessens F, Peeters B, Heyns W, Verhoeven G, Rombauts W 1993 Proteins interacting with an androgen-responsive unit in the C3(1) gene intron. Mol Cell Endocrinol 94:165–172[CrossRef][Medline]
  403. Chen H, Zhang P, Radomska HS, Hetherington CJ, Zhang DE, Tenen DG 1996 Octamer binding factors and their coactivator can activate the murine PU.1 (spi-1) promoter. J Biol Chem 271:15743–15752[Abstract/Free Full Text]
  404. Chong T, Apt D, Gloss B, Isa M, Bernard HU 1991 The enhancer of human papillomavirus type 16: binding sites for the ubiquitous transcription factors oct-1, NFA, TEF-2, NF1, and AP-1 participate in epithelial cell-specific transcription. J Virol 65:5933–5943[Abstract/Free Full Text]
  405. Currie RA, Eckel RH 1992 Characterization of a high affinity octamer transcription factor binding site in the human lipoprotein lipase promoter. Arch Biochem Biophys 298:630–639[CrossRef][Medline]
  406. Wu GD, Lai EJ, Huang N, Wen X 1997 Oct-1 and CCAAT/enhancer-binding protein (C/EBP) bind to overlapping elements within the interleukin-8 promoter. The role of Oct-1 as a transcriptional repressor. J Biol Chem 272:2396–2403[Abstract/Free Full Text]
  407. Li-Weber M, Salgame P, Hu C, Davydov IV, Laur O, Klevenz S, Krammer PH 1998 Th2-specific protein/DNA interactions at the proximal nuclear factor-AT site contribute to the functional activity of the human IL-4 promoter. J Immunol 161:1380–1389[Abstract/Free Full Text]
  408. Duncliffe KN, Bert AG, Vadas MA, Cockerill PN 1997 A T cell-specific enhancer in the interleukin-3 locus is activated cooperatively by Oct and NFAT elements within a DNase I-hypersensitive site. Immunity 6:175–185[CrossRef][Medline]
  409. Kamps MP, Corcoran L, LeBowitz JH, Baltimore D 1990 The promoter of the human interleukin-2 gene contains two octamer- binding sites and is partially activated by the expression of Oct-2. Mol Cell Biol 10:5464–5472[Abstract/Free Full Text]
  410. Tseng YH, Schuler LA 1998 Transcriptional regulation of interleukin-1{beta} gene by interleukin-1{beta} itself is mediated in part by Oct-1 in thymic stromal cells. J Biol Chem 273:12633–12641[Abstract/Free Full Text]
  411. Lopez-Rodriguez C, Zubiaur M, Sancho J, Concha A, Corbi AL 1997 An octamer element functions as a regulatory element in the differentiation-responsive CD11c integrin gene promoter: OCT-2 inducibility during myelomonocytic differentiation. J Immunol 158:5833–5840[Abstract]
  412. Liang Y, Carr LG 1996 Identification of an octamer-1 transcription factor binding site in the promoter of the mouse mu-opioid receptor gene. J Neurochem 67:1352–1359[Medline]
  413. Khodadoust MM, Khan KD, Bothwell AL 1999 Complex regulation of Ly-6E gene transcription in T cells by IFNs. J Immunol 163:811–819[Abstract/Free Full Text]
  414. Moriuchi H, Moriuchi M, Fauci AS 1997 Cloning and analysis of the promoter region of CCR5, a coreceptor for HIV-1 entry. J Immunol 159:5441–5449[Abstract]
  415. Yamamoto K, Takeshima H, Hamada K, Nakao M, Kino T, Nishi T, Kochi M, Kuratsu J, Yoshimura T, Ushio Y 1999 Cloning and functional characterization of the 5'-flanking region of the human monocyte chemoattractant protein-1 receptor (CCR2) gene. Essential role of 5'-untranslated region in tissue-specific expression. J Biol Chem 274:4646–4654[Abstract/Free Full Text]
  416. Nagasawa T, Takeda T, Minemura K, DeGroot LJ 1997 Oct-1, silencer sequence, and GC box regulate thyroid hormone receptor {beta}1 promoter. Mol Cell Endocrinol 130:153–165[CrossRef][Medline]
  417. Scarlett CO, Scheller A, Thompson E, Robins DM 1997 Involvement of an octamer-like sequence within a crucial region of the androgen-dependent Slp enhancer. DNA Cell Biol 16:45–57[Medline]
  418. Rosfjord E, Rizzino A 1994 The octamer motif present in the Rex-1 promoter binds Oct-1 and Oct-3 expressed by EC cells and ES cells. Biochem Biophys Res Commun 203:1795–1802[CrossRef][Medline]
  419. Wang Z, Melmed S 1998 Functional map of a placenta-specific enhancer of the human leukemia inhibitory factor receptor gene. J Biol Chem 273:26069–26077[Abstract/Free Full Text]
  420. Tverberg LA, Russo AF 1993 Regulation of the calcitonin/calcitonin gene-related peptide gene by cell-specific synergy between helix-loop-helix and octamer-binding transcription factors. J Biol Chem 268:15965–15973[Abstract/Free Full Text]
  421. Sebastian S, White JA, Wilson JE 1999 Characterization of the rat type III hexokinase gene promoter. A functional octamer 1 motif is critical for basal promoter activity. J Biol Chem 274:31700–31706[Abstract/Free Full Text]
  422. Schwachtgen JL, Remacle JE, Janel N, Brys R, Huylebroeck D, Meyer D, Kerbiriou-Nabias D 1998 Oct-1 is involved in the transcriptional repression of the von Willebrand factor gene promoter. Blood 92:1247–1258[Abstract/Free Full Text]
  423. Wright KL, Ting JP 1992 In vivo footprint analysis of the HLA-DRA gene promoter: cell-specific interaction at the octamer site and up-regulation of X box binding by interferon {gamma}. Proc Natl Acad Sci USA 89:7601–7605[Abstract/Free Full Text]
  424. Hermanson GG, Briskin M, Sigman D, Wall R 1989 Immunoglobulin enhancer and promoter motifs 5' of the B29 B-cell-specific gene. Proc Natl Acad Sci USA 86:7341–7345[Abstract/Free Full Text]
  425. Pfisterer P, Konig H, Hess J, Lipowsky G, Haendler B, Schleuning WD, Wirth T 1996 CRISP-3, a protein with homology to plant defense proteins, is expressed in mouse B cells under the control of Oct2. Mol Cell Biol 16:6160–6168[Abstract]
  426. Kim MH, Peterson DO 1995 Oct-1 protein promotes functional transcription complex assembly on the mouse mammary tumor virus promoter. J Biol Chem 270:27823–27828[Abstract/Free Full Text]
  427. Thevenin C, Lucas BP, Kozlow EJ, Kehrl JH 1993 Cell type- and stage-specific expression of the CD20/B1 antigen correlates with the activity of a diverged octamer DNA motif present in its promoter. J Biol Chem 268:5949–5956[Abstract/Free Full Text]



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