help button home button Endocrine Society Endocrine Reviews
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dahia, P. L. M.
Right arrow Articles by Grossman, A. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dahia, P. L. M.
Right arrow Articles by Grossman, A. B.
Right arrowPubmed/NCBI databases
*Substance via MeSH
Endocrine Reviews 20 (2): 136-155
Copyright © 1999 by The Endocrine Society

The Molecular Pathogenesis of Corticotroph Tumors

P. L. M. Dahia1 and A. B. Grossman

Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom


    Abstract
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 

I. Introduction
A. Origin of tumors: hypothalamus vs. pituitary
B. Clonality of pituitary tumors
II. Protooncogenes
III. Tumor Suppressor Genes
A. p53
B. p16/CDKN2/MTS1/INK4 and Rb1
C. p27/KIP1/CDKN4
D. MEN1
E. hZAC
F. NM23
G. Other tumor suppressor genes
IV. Specific Genes
A. Regulatory receptor genes
B. Cytokines and growth factors
C. Developmental genes
V. Miscellaneous
A. Other genes
B. Methylation
VI. Perspectives: Old and New Tools for Understanding Pituitary Pathogenesis
A. Transgenic/knockout animal models
VII. Conclusions


    I. Introduction
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 
TO FULLY understand the ontogeny of corticotroph tumors, some understanding is required of normal pituitary cell development. Pituitary ontogeny is directed by a complex myriad of factors, including the homeobox genes, that are expressed at distinct and highly specific phases of pituitary development (1). The anterior pituitary gland arises embryologically from Rathke’s pouch, while the posterior lobe originates from the ventral hypothalamus. Interactions between the two tissues are essential for their differentiation. Once committed to a pituitary ’fate,’ the cells from Rathke’s pouch proliferate and differentiate into specific cell lineages that secrete POMC, GH, PRL, TSH, FSH, and LH (1) (Fig. 1Go). Control of pituitary cell proliferation and gene expression is provided by hypothalamic peptides and their specific receptors located in the pituitary. The gene encoding the {alpha}-glycoprotein subunit, {alpha}-GSU, the common component of the heterodimeric TSH, LH, and FSH, is activated very early in pituitary development. Activation of the transcription factor Pit-1 mRNA occurs as an organ-specific event, initially in all five cell types (2). However, the Pit-1 protein is detected in only three cell types in the mature pituitary gland: the lactotrophs, somatotrophs, and thyrotrophs, but is not found in either gonadotrophs or corticotrophs (2). Interactions between specific activating and restricting factors with Pit-1 in distinct temporal patterns contribute to defining the specificity of the three cell lineages. However, much less is known about the origin and maturation of the corticotroph, although there is evidence from studies in mice that commitment to the corticotroph might occur even earlier than the expression of {alpha}-GSU (3, 4). The homeobox gene Ptx1 is expressed in most cells of Rathke’s pouch at an early stage of pituitary development, and before the final differentiation of hormone-producing cells. Thus, Ptx1 seems to play a role in the differentiation of pituitary cells and possibly also in the formation of the specific gland. In the adult pituitary, by contrast, Ptx1 appears to be recruited for cell-specific transcription of the POMC gene (4). Pituitary leukemia-inhibitory factor (LIF) is expressed early in the development of the pituitary and enhances POMC expression in synergism with CRH (5). However, LIF exerts an antiproliferative effect on the corticotroph. These interactions between various transcription factors and hypothalamic peptides in coordinating pituitary embryogenesis are outlined in Fig. 1Go. It is the purpose of this review to explore our current knowledge in understanding how this process may become deranged in the development of corticotroph adenomas.



View larger version (18K):
[in this window]
[in a new window]
 
Figure 1. Simplified schematic representation of pituitary ontogeny with putative factors involved in differentiation of specific lineages.

 
A. Origin of tumors: hypothalamus vs. pituitary
Cushing’s disease, pituitary-dependent Cushing’s syndrome, is the hypercortisolemic state secondary to excess or dysregulated ACTH (corticotropin) secretion caused by a corticotropin-secreting adenoma (6, 7, 8). ACTH production by the adenoma occurs in a semiautonomous manner, in which one of the principal biochemical features is a resetting of the hypothalamo-pituitary-adrenal (HPA) feedback such that ACTH is secreted in the presence of abnormally high levels of circulating cortisol (9). There has long been debate as to the primary origin of pituitary tumors in general, specifically, as to whether they arise primarily from defects of the hypothalamus or the pituitary. It has been argued that many of the associated endocrine changes seen in Cushing’s disease, particularly abnormalities in the growth, pituitary-gonadal, and thyroid axes, suggest primary hypothalamic dysfunction. Equally, the occasional lack of an identifiable adenoma at surgery, and instances of tumor recurrence after apparent complete removal of an identified tumor, might also suggest some form of preexisting hypothalamic ’over-drive.’ However, favoring a fundamentally pituitary origin of Cushing’s disease are several lines of evidence: the generally high cure rate after removal of a distinct adenoma, the absence of identifiable corticotroph hyperplasia surrounding the tumor, and, most importantly, the characterization of the monoclonal status of the majority of adenomas assessed (see below) (10, 11, 12, 13). It has also become apparent in recent years that most, if not all, of the associated neuroendocrine changes are a manifestation of cortisol excess, and normalize when cortisol levels are medically or surgically brought within the normal range. The great majority of patients with Cushing’s disease are thus thought to harbor distinct ACTH-secreting pituitary adenomas.

Corticotroph tumors are of special interest in understanding the process of oncogenesis, as many of the biochemical characteristics of such tumors show only relative, rather than absolute, abnormalities compared with the normal corticotroph, which might suggest that the somatic defect that occurs in the corticotroph clone is quite subtle. This renders the corticotroph adenoma a very interesting model of tumor formation and one that should be amenable to systematic analysis. We will attempt to summarize and integrate the current knowledge on the potential involvement of a variety of molecular derangements, and highlight some of the more fruitful areas of present and future research.

B. Clonality of pituitary tumors
As mentioned above, the debate over the origin of pituitary tumors has settled for a local, pituitary origin for at least the majority of tumors, mainly as a result of the clonality studies. Clonal analysis substantiates the fundamental distinction between a polyclonal proliferation in response to a stimulatory factor vs. a monoclonal expansion of a genetically aberrant cell (14, 15, 16, 17). Clonality studies have shown that most of the pituitary adenomas tested are monoclonal in origin, compatible with the hypothesis that somatic defects precede clonal expansion of these cells and are likely to be involved in the tumorigenesis process (11). In the few cases where the samples were found to be polyclonal, admixture of nontumoral cells in the tumor preparation appears to have accounted for the artifactual polyclonality of at least some of these cases (10). It is possible that a minority of such tumors acquire a monoclonal pattern later in their development, after a prolonged phase of polyclonal growth. The mechanisms differentially regulating tissue growth in the monoclonal vs. "polyclonal" pituitary adenomas are still unknown.


    II. Protooncogenes
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 
Several protooncogenes have been tested for abnormalities in corticotroph tumors, most of which have mainly been found to be negative. While some genes, such as RAS, c-ERB2/neu, c-MYC, and PKC have been associated with more aggressive pituitary tumors, these findings do not appear to relate specifically to the corticotroph lineage (18, 19, 20, 21). Other genes that have been tested and shown to be unaltered in the majority of pituitary tumors are RET (22), c-MYB, and c-FOS (23). Furthermore, mutations of genes encoding for the stimulatory Gs{alpha}, inhibitory Gi{alpha}, and phospholipase C-mediated (Gq{alpha}) subunits of the G protein complex, which contribute to pituitary signaling, do not seem to be involved to any significant extent in the pathogenesis of corticotropinomas (24, 25). This is in contrast to the situation in somatotropinomas, where approximately 40% of the tumors carry mutations of the stimulatory {alpha}-subunit of the G protein complex (26). The reasons for this tissue specificity are not clear.

A recently identified rat gene that appears to have strong transforming properties is the pituitary tumor-transforming gene (PTTG), which has been cloned by differential display analysis: a unique sequence was found to be expressed in rat GH- and PRL-secreting tumor cell lines, while it was absent in normal pituitary and in an osteogenic sarcoma cell line (27). In vitro studies have shown that this product, which spans 199 amino acids with no homology to known domains, is able to induce cell transformation and, interestingly, inhibits cell proliferation (27). The human homolog of PTTG has now been cloned and found to possess transforming properties in vivo and in vitro (28). Initial studies have suggested that PTTG functions via SH3-mediated signals and induces fibroblast growth factor (FGF) expression in transfected cells. While an initial analysis has not identified mutations in pituitary tumors, increased expression of PTTG was found in more aggressive pituitary tumors and other human tumors and cell lines (28, 29). Further studies aiming at a functional characterization of the role of the PTTG gene in pituitary cell proliferation and its association with more aggressive tumor phenotypes are warranted.


    III. Tumor Suppressor Genes
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 
A. p53
The p53 gene has been considered the most frequently mutated gene in human malignancies, being abnormal in approximately 50% of all human malignant tumors (30, 31). Its product has tumor suppressor activity by blocking the progression of the cell cycle from G1, principally by activating p21, which in turn inhibits certain cyclin-dependent kinases (32, 33, 34, 35, 36, 37, 38). Mutations of the p53 gene have been found to cluster in the DNA-binding domain (DBD) of the protein, represented by exons 5–8 of the gene, and most of the mutation screening studies have concentrated on this ’hot spot’ region (30, 31, 39).

Several studies investigating p53 status in corticotroph tumors are available. While more than 50% of both invasive and noninvasive corticotroph adenomas from one series showed abnormal p53 immunostaining (40), no mutations were found in an independent series examined at the nucleotide level (41, 42). These apparent discordant results of sequence and protein analysis may be explained by the fact that mutations might have been located outside the region of the p53 gene screened. Alternatively, the positive p53 protein staining observed, suggestive of a p53 abnormality, could have been due to increased expression of the wild-type p53 protein as a result of its up-regulation by a regulatory gene such as MDM2 (43, 44), rather than a direct disruption of the p53 gene. On the basis of the existing data, the potential role of p53 as a major contributor to pituitary tumorigenesis, in particular with regard to the corticotroph lineage, cannot be entirely excluded but appears unlikely.

Recently, a gene was cloned on chromosome 1p35, one of the regions found to be a target for loss of heterozygosity (LOH) in endocrine tumors (45, 46, 47, 48). The novel gene, p73, encodes a product that not only resembles p53 structurally, but also appears to interact with it by forming heterodimers (48, 49). Although no structural abnormalities of this gene were found in an initial series of neuroblastoma cell lines and primary tumors with LOH at the 1p35–36 region, it has been noted that most of the samples examined express a single p73 allele, even when the two alleles were present in the germline (48). This p73 monoallelic expression appears to represent a novel mechanism of inactivation of a tumor suppressor gene, and further studies are needed to confirm this initial observation and unravel the potential role of the p73 gene in human tumors.

Another tumor suppressor gene whose product also appears to interact with p53 has recently been identified (50). The novel gene, p33ING1, interacts with p53 in an interdependent manner in several of known p53 functions, such as negative regulation of cell proliferation, apoptosis, cell anchorage, and control of cellular aging, as well as mediation of p21 transactivation. Because of its role in the p53 signaling pathway, it will be of interest to verify whether p33ING1 is implicated in the abnormal p53 expression seen in certain tumors, in particular corticotroph adenomas.

Additional p53-related genes have now been reported (51, 52, 53). While these genes are potentially interesting targets for studies in human tumors, their role in pituitary signaling and/or tumorigenesis has not as yet been explored.

B. p16/CDKN2/MTS1/INK4 and Rb1
The Rb1 gene product plays an essential role in regulating the progression of the cell cycle (54, 55, 56, 57). In its dephosphorylated form, the Rb1 product blocks cell cycle progression from G1 to S phase. Progression of the cycle occurs when the Rb product is phosphorylated by complexes formed between specific subtypes of cyclins and cyclin-dependent kinases (cdk), acting downstream of p53 and p21 (58). Interest in the potential role of the RB1 gene in pituitary tumors arose from knockout mice models: all animals with one inactive RB1 allele developed pituitary tumors of the intermediate lobe (59, 60, 61). However, attempts to identify RB1 gene mutations have failed to show abnormalities of this gene in human tumors of any lineage (62, 63, 64). LOH at 13q14, the RB1 locus, has been identified in all 13 cases of a series of malignant or highly invasive pituitary tumors, in particular of the nonsecreting type, suggesting that another, yet unknown, tumor suppressor gene located in this region may be involved in pituitary tumorigenesis (23, 64, 65, 66), specifically those associated with a more aggressive phenotype.

The p16 gene has arisen as a frequent target for inactivation in several human tumors (67): it maps to chromosome 9p21, a region frequently deleted in human tumors. Through its regulatory role of the cyclin-cdk complex, in particular cdk 4, the p16 product exerts inhibitory effects on cell cycle progression from G1 to S phase (68, 69, 70, 71). Cyclin D-cdk 4 complexes phosphorylate the retinoblastoma product, rendering it inactive and therefore unable to block cell cycle progression (72). In the absence of the p16 protein, the inhibitory loop ceases to exist, and cell cycle progression becomes unrestrained, giving rise to tumor growth and/or progression.

Because of the interactive pathways of p16 and Rb1 function, it was postulated that disruption of either product might also occur in an interactive manner. In particular, an apparent inverse correlation of their alterations has been observed in certain human tumors, such as lung carcinomas, in which high levels of p16 protein are seen in Rb1-disrupted tumors, while low or undetectable p16 protein occurs in tumors carrying wild-type Rb1 (73). It was therefore postulated that pituitary tumors could give rise to a disrupted Rb1 pathway secondary to a change in p16 function. Indeed, all 25 pituitary tumors from a series in which a nonspecified number of histological subtypes were represented failed to express the p16 protein product (74). More recently, a study has indicated that the mechanism involved in p16 silencing in the majority of pituitary tumors lacking p16 protein expression is hypermethylation of the promoter region of the gene (75). Full characterization of the clinical and biochemical features of pituitary tumors with a hypermethylated p16 gene, as compared with those with full p16 activity, awaits further study. In keeping with the finding of abnormal transcription of the p16 gene without genomic deletions, it has been shown that the p16 locus is intact in the majority of pituitary adenomas. However, about one-third of pituitary tumors from one series, including invasive and noninvasive forms, have been shown to have LOH at the 9p21 region (76). This finding suggests that another tumor suppressor gene located in this region might play a role in pituitary tumorigenesis.

C. p27/KIP1/CDKN4
It has recently been reported that mice with a genomic "knockout" of the p27KIP1 gene develop multiorgan hyperplasia resulting in increased animal size (77, 78, 79). Similar to the RB1 knockout model, the P27 null mice have shown pituitary tumors that originate from intermediate lobe corticotrophs although, rather surprisingly, no other neoplasms were seen.

The p27KIP1 gene, like p16, is a member of the cyclin-kinase inhibitor family of proteins (80, 81, 82, 83, 84). The p27 protein specifically inhibits complexes formed between cdk2 and cyclin E, required for entry into S phase from late G1, and also between D-type cyclins and cdk4/cdk6 (85, 86, 87). These latter complexes mediate the phosphorylation of the Rb protein, which renders it inactive, allowing for the cell cycle to progress from mid-G1. Due to the physiological interaction between p27 and Rb1 pathways, and also from the similarities in the phenotype of either knockout model, p27KIP1 was clearly a possible candidate gene for pituitary tumorigenesis. We therefore recently examined 23 pituitary tumors, 21 of which were ACTH-secreting, including two with intermediate lobe features, for p27 abnormalities (88). Apart from a previously known polymorphism in the coding region of the gene, no structural alterations were found in the tumors. Also, no specific changes in p27KIP1 transcription were detected in the tumors as compared with normal pituitaries. At the protein level, most of the tumor samples showed apparently normal p27 staining (although in our more recent ongoing studies we have also noted a relative decrease in p27 protein expression in corticotropinomas as compared with other tumor types). However, two of three malignant corticotropinomas examined, as well as one malignant prolactinoma, were negative for p27 immunocytochemically. This might indicate that p27 inactivation may be related to more aggressive histological subtypes of ACTH-secreting and possibly other pituitary tumors and may be a prognostic factor in such tumors. It has been suggested that p27 immunostaining may be related to more aggressive subtypes of colon and breast tumors, also indicating its potential role as a prognostic marker in such tumors (89, 90, 91, 92). As the distinction between malignant and benign tumors is extremely difficult for endocrine neoplasms, the existence of a marker that helps identify aggressive types in a more premature phase of tumor progression (before the occurrence of metastases) may become a powerful tool in therapeutic planning and prognostic assessment of pituitary tumors. Other recent studies on the potential role of p27KIP1 in pituitary tumorigenesis have confirmed our findings of a lack of abnormalities at the nucleotide level (93, 94) and lower p27 protein levels in the malignant forms of tumors in comparison with normal pituitaries and benign adenomas (95, 96). One of these studies (95) suggested that the differentiation between benign and malignant tumors might be more quantitative than qualitative, since a graduated diminution of p27 protein levels was observed progressing from normal to benign to malignant samples. These data also suggest that the p27KIP1 mechanism of inactivation is predominantly a posttranslational event. In support of this hypothesis is the finding of high levels of p27 degradation in proliferative cells (97, 98, 99). However, it still remains unclear as to why both RB1 and p27KIP1 mice knockouts develop corticotropinomas, but abnormalities of these genes and their products are not seen in human Cushing’s disease. Perhaps these gene products may exert more relevant regulatory functions in other animal species, such as canine and equine models of Cushing’s disease, where the tumors more clearly arise from the pituitary pars intermedia (100, 101, 102), similar to the mouse tumor location. We hope, however, that continuing studies into the relative expression of p27 in corticotroph, as opposed to adenomas of other cell lineages, will help to explain these puzzling findings.

The chromosome 12p13 region, where p27KIP1 is located, has been defined as a common target for genomic alterations in human malignancies. Using polymorphic markers located at the 12p13 area, we did not find LOH in any pituitary tumor analyzed (88). While seeking LOH in the same area, another study (94) detected, instead, chromosome 12 trisomy in five of eight samples that showed abnormal allelic ratios of polymorphic markers spanning the entirety of chromosome 12. However, as not all abnormal samples were available for fluorescence in situ hybridization analysis, it is possible that some degree of contamination with background normal cells might have accounted for the abnormal allelic ratios seen in some samples. The actual incidence of trisomy of chromosome 12 in pituitary tumors and the potential correlation with histological subtypes awaits further studies.

A recent study reporting a mouse model deficient in the cell-cycle inhibitor p18 revealed the presence of pituitary adenomas of the intermediate lobe (103), in a similar fashion to the p27 knockout mice mentioned above. Mice lacking both p18 and p27 invariably died from pituitary adenomas by 3 months of age. It appears, therefore, that p18 and p27 function in a collaborative manner to suppress pituitary tumorigenesis in mice. The role of p18 in human pituitary tumors still remains to be determined, but it will certainly be relevant to characterize whether, similar to the p27 and Rb knockouts, the mouse model differs from the human in yet another protein involved in the Rb-signaling pathway.

D. MEN1
While most often presenting as sporadic tumors, corticotroph adenomas may be occasionally familial, usually as part of the multiple endocrine neoplasia type 1 syndrome (MEN 1). In this setting, there is usually an association of pituitary tumors with parathyroid and pancreatic tumors as well as less common features, such as carcinoids, adrenal tumors, lipomas, angiofibromas and ependymomas (104, 105).

The susceptibility gene for MEN 1 has been mapped to chromosome 11q13 by linkage analysis (106, 107). The MEN1 gene has been recently identified by positional cloning (108, 109, 110, 111). This gene encodes a 610-amino acid protein product named menin that contains no recognizable structural or functional domains. Mutations of the MEN1 gene have now been reported in a variable number of MEN1 families, with the overall incidence of mutations ranging from 59% to more than 80% of the families studied (108, 109, 112, 113, 114). Although no functional studies involving mutant proteins are available to date, the mutations observed are expected to truncate menin. This finding has important consequences for the screening of members of MEN 1 kindreds. Since 10–30% of sporadic pituitary tumors have also been found to have LOH at the MEN1 locus (23, 115, 116, 117), suggesting that MEN1 acts as a tumor suppressor gene, studies looking for mutations of the MEN1 gene in sporadic pituitary adenomas are relevant. Unlike the findings in MEN 1-related tumors, several reports on the status of MEN1 in sporadic pituitary adenomas have revealed a very low incidence of mutations in such samples, irrespective of cell lineage (113, 118, 119). The expression of MEN1 mRNA also appears to be essentially normal in most sporadic tumors evaluated, including a small number of corticotropinomas (120, 121). The lack of down-regulation of the MEN1 gene was observed despite the presence of LOH at the MEN1 locus in some tumors. Furthermore, while mutations have been detected in all exons of the MEN1 gene, no clear genotype-phenotype correlation has been characterized (122).

Recent studies have demonstrated that menin localizes to the cell nucleus (123). Two nuclear localization signals (NLS) were identified in the C terminus of the protein, a region not found to be targeted by naturally occurring missense mutations and in-frame deletions. However, truncated protein products, resulting from frameshift and nonsense mutations, would lack at least one of these NLS, suggesting that they are important for the full activity of menin. While the protein function is still elusive, its nuclear localization suggests that it might be involved in regulating transcription of responsive elements.

E. hZAC
A novel zinc finger protein with tumor suppressor properties has recently been identified and mapped to chromosome 6q24–25 (124, 125). This gene, named hZAC or LOT1 by two independent groups, is the human homolog of a recently isolated transcript from the AtT20 mouse corticotropinoma cell line. By a functional expression-cloning technique, this gene was found to display a unique expression pattern: the pituitary was found to express the highest levels of zac1 transcript among several different tissues examined (126). Interestingly, this functional expression technique also resulted in the isolation of wild-type p53 clones, suggesting that the two products possibly interact. zac1 and p53 were found to induce expression of the gene encoding the type I receptor PACAP-R1, possibly indicating its role in regulating cAMP-mediated pathways. The human homolog has been found to share the same tissue distribution as the mouse gene, with the pituitary, kidney, placenta, and adrenals showing the highest levels of expression (124). Functional studies revealed that the antiproliferative properties of hZAC are related to its ability to induce apoptosis and cell cycle arrest in G1, similar to p53 (124). This is the first human gene structurally unrelated to p53 that shares its apoptotic and cell cycle-blocking functions. Recently, hZAC expression was noted to be absent in ovarian tumor cell lines (125), and the hZAC1 locus is a commonly deleted area in several human cancers. However, it remains to be established whether this gene plays a role in pituitary tumorigenesis.

F. NM23
A gene encoding for a purine-binding factor with tumor suppressor properties, NM23, has been reported to be down-regulated in multiple invasive human cancers (127, 128, 129, 130, 131). One series of pituitary tumors has been examined for NM23 abnormalities: while no nucleotide alterations have been found, the more aggressive tumors showed reduced expression of one isoform, H2, of the NM23 transcript (132). In particular, an association was found between low H2 levels and cavernous sinus invasion. Whether this phenomenon of down-regulation represents cause or effect of the more aggressive tumor behavior remains to be established.

G. Other tumor suppressor genes
In the course of investigating the potential role of the RB1 gene in pituitary tumors, it had been noted that a subset of such tumors have LOH at the chromosome subregion 13q14 (23, 62, 64, 65). While the RB1 gene has been excluded as the target for deletion in that region, other tumor suppressor genes lying in the 13q14 area have been investigated for their potential role in pituitary tumorigenesis. One such gene is the BRCA2 tumor suppressor, which lies within 25 centiMorgans of the RB1 locus (66). Only two pituitary tumors, neither of which was a corticotropinoma, were found to have LOH at markers spanning both the BRCA2 and RB1 loci (66). These results suggest that yet another tumor suppressor gene in this area might be associated with the development of pituitary tumors.

A study designed to verify potential tumor suppressor loci associated with malignant pituitary tumorigenesis revealed LOH at chromosomes 1p, 3p, 10q26, 11q13, and 22q12 (133). Candidate genes at these regions might potentially be involved in determining or contributing to a more aggressive phenotype in pituitary tumors (23, 133).


    IV. Specific Genes
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 
A. Regulatory receptor genes
Certain oncogenes and tumor suppressor genes examined for their role in neoplasia are associated with broad, nonspecific cell growth regulation and may therefore affect any cell type. On the other hand, genes encoding for proteins that participate in tissue-specific mechanisms of cell regulation would appear to be potentially good candidates for tumorigenesis of defined cell types.

Corticotrophs are regulated by several hormones whose actions within the cell take place through specific receptors (134, 135, 136, 137, 138, 139, 140, 141). ACTH secretion and cell growth are determined by a complex balance that regulates stimulatory impulses, such as the CRH receptor (CRH-R), the vasopressin receptor (specifically, the type 1b or type 3 receptor, V3R), and the LIF receptor (LIF-R), as well as inhibitory regulators, such as the glucocorticoid receptor (GR). While POMC and ACTH secretion might be associated with corticotroph proliferation under the activity of certain factors, occasionally opposing signals result (Table 1Go). Several other receptors have been found to be expressed by the corticotroph, although their actions do not appear to be specific to this cell type. The potential role of the more corticotroph-specific receptor-encoding genes has recently been assessed, and the results are briefly discussed here. In addition, other receptors with potentially important roles in corticotroph regulation are mentioned.


View this table:
[in this window]
[in a new window]
 
Table 1. Effect of some hormone receptors, transcription factors, and cytokines discussed in this review on ACTH secretion and corticotroph proliferation (see text)

 
1. Vasopressin type 3 receptor (V3R). The existence of a pituitary-specific vasopressin receptor has long been suspected and appeared from several studies (137, 142, 143, 144, 145, 146) to share some of the properties of the vascular subtype (V1R), such as the activation of a phospholipase C pathway (147, 148). The V3R receptor was cloned in 1994 (149, 150) and shown to be a seven-transmembrane domain receptor type, with a relatively low degree of homology to types 1 and 2 vasopressin receptors (151, 152, 153, 154). The receptor agonist, arginine vasopressin (AVP), principally stimulates ACTH secretion via activation of the pituitary V3R, but may also act in part via the hypothalamus, stimulating CRH secretion (143, 155, 156, 157, 158). Similar to other endocrine models (for a review, see Ref. 159), gain-of-function mutations of the V3R gene would be expected to constitutively activate its signaling pathway, potentially giving rise to ACTH-secreting adenomas. However, screening of the whole coding region of the V3R gene did not reveal any mutations of 12 ACTH-secreting tumors analyzed, including 11 pituitary and 1 ectopic ACTH secretor (160). In spite of this, all tumors demonstrated overexpression of the V3R gene by RT-PCR as compared with normal pituitaries obtained at autopsy (Fig. 2Go).



View larger version (23K):
[in this window]
[in a new window]
 
Figure 2. Ethidium bromide-stained 10% polyacrylamide gel of V3R and glyceraldehyde phosphodehydrogenase duplex RT-PCR, the lower band representing V3R. P1 and P2 are two normal pituitaries; T1–T5 are ACTH-secreting tumors; N is negative control and M is a size marker. [Reproduced with permission from P. L. M. Dahia et al.: J Clin Endocrinol Metab 81:1768–1771, 1996 (160 ). © The Endocrine Society.]

 
It has been known that a V2-derived agonist, desmopressin, commonly used for the treatment of central causes of diabetes insipidus, is able to elicit ACTH increase in patients with Cushing’s disease, but not in normal individuals, and occasionally in patients with ectopic sources of ACTH secretion (161, 162, 163). It is possible that the desmopressin activates this over-expressed V3R population in adenomatous corticotrophs. Alternatively, or probably in addition, V2-type receptors were found to be abundantly expressed in the majority of corticotroph tumors, which may also account in part for the abnormal response to desmopressin observed in those tumors (160). However, studies with rats have recently demonstrated that administration of glucocorticoids results in up-regulation of the V3R receptor (164). Hence, it is most probable that the change in expression of V3R, and possibly also V2R, is a consequence of the high levels of circulating corticosteroid rather than the cause of the hypersecretory state in the corticotroph tumors analyzed. However, the debate over the role of an increased expression of V3R in corticotroph tumors has not yet been settled. In support of the hypothesis that V3R overexpression might, in fact, reflect a causative event in corticotroph tumorigenesis, is the finding that a moderate increase in V3R number leads to a proliferative signal (165) (see below). It has also been found that not only pituitary-originated, but also ectopic ACTH-secreting tumors, are associated with high levels of V3R (160). The single ectopic ACTH-secreting tumor in our series was a bronchial carcinoid, where positive responses to desmopressin had been observed in vivo before the surgery. Furthermore, we have also reported another bronchial carcinoid that expressed the V3R and responded to desmopressin both in vivo and in vitro (166) (Fig. 3Go). In summary, while V3R gene mutations do not seem to be a major feature of corticotroph tumors, the high transcription levels of this gene in the tumors may account, in part, for their response to desmopressin stimulation.



View larger version (70K):
[in this window]
[in a new window]
 
Figure 3. Ethidium bromide-stained agarose gel of V2R (top band) and V3R (bottom band) PCR products. Lane 1 is a size marker; lane 2, a 10-fold concentrated normal pituitary; lane 3, a normal pituitary; lane 4, the reported bronchial carcinoid ACTH-secreting tumor; lane 5, a corticotroph tumor; and lane 6 is a PCR blank control [Reproduced with permission from W. Arlt et al.: Clin Endocrinol (Oxf) 47:623–627, 1998 (166 ). © Blackwell.]

 
Among the most potent stressful activators of the hypothalamic-pituitary-adrenal (HPA) axis are psychological stimuli (167), with the patterns of AVP and CRH release varying according to the nature of the stressor involved. In many paradigms of chronic stress, a predominant role of AVP in facilitating the release of ACTH is observed, while CRH mainly exerts only a permissive role in such secretion (167). In the hypothalamus, an increased number of CRH neurons coexpressing AVP, as well as increased AVP mRNA expression, have been noted (168, 169). While prolonged stress is associated with reduced CRH receptor number in the pituitary, V3R receptors have been shown to be up-regulated in certain stress conditions (170). It has long been suggested that anxiety and depressive disorders are common preexisting features in patients with Cushing’s disease (171), but the reasons for this finding remain elusive. Although there is some circumstantial evidence to suggest that AVP plays a critical role in the regulation of the HPA axis in depressive disorders, a direct proof of this predominant AVP-mediated role in contributing to the development of a pituitary tumor is still lacking. It is not known, for example, whether chronic activation of the HPA axis in such states would facilitate the growth advantage of responsive cells and ultimately lead to clonal growth of a corticotroph. In this hypothetical model, an AVP-predominant system, compatible with chronic stress, would require that V3R-mediated corticotroph stimulation should also be associated with a mitogenic signal. However, the complexity of V3R signaling, which varies according to the level of receptor expression and is associated with a diminished proliferation signal at high levels of receptor expression (165), is not directly compatible with this model. Nevertheless, the possible proliferative effects of the endogenous overexpression of V3R in corticotroph tumors has not been examined in detail. Indeed, there is some suggestion from the literature that a preexisting corticotroph hyperplastic state might underlie the development of certain ACTH-secreting tumors (172). It therefore remains to be determined whether psychological stress is involved in the cascade of events leading to corticotroph tumor growth in vivo.

2. GR. One of the hallmarks of ACTH-secreting tumors is their resistance to corticosteroid feedback, which is partially present in pituitary tumors but is more pronounced in ectopic ACTH secretors (8, 173, 174). This differential regulation suggests that distinct mechanisms are involved in determining the glucocorticoid resistance in these two groups of tumors.

Corticosteroids act via activation of the ubiquitously expressed type II GR (175, 176, 177). The human GR is known to produce two transcripts as a result of alternative splicing of the gene: GR-{alpha} and GR-ß (178, 179, 180). These highly homologous subforms, with 777 and 742 amino acids, respectively, differ only at their carboxy terminus. This difference renders GR-ß unable to bind glucocorticoids. Only recently has the role of GR-ß been explored in more detail, and some evidence has suggested that it acts as a negative regulator of the classical GR-{alpha} by forming heterodimers (181, 182, 183, 184). Derangements of GR-{alpha} have been shown to be associated with glucocorticoid resistance syndromes (185, 186, 187, 188). Furthermore, the wide diversity of phenotypes attributed to the glucocorticoid resistance state has recently been suggested to be related to the type of mutation found in the GR gene structure: different point mutations in the GR gene can affect distinct pathways of gene regulation in a differential fashion (189). Hence, disruption of the GR gene, either at the structural or transcription level, leading to abnormal function of the receptor could potentially contribute to the pituitary-specific glucocorticoid resistance seen in corticotroph adenomas. In fact, a mutation in the DBD of the GR gene has been found in the tumoral tissue of one patient with Nelson’s syndrome (190), an aggressive form of corticotroph adenoma that had its growth accelerated by removal of the adrenal glands in a patient with a pituitary source of dysregulated ACTH secretion (191). A frameshift mutation expected to create a truncation in the GR product was hypothesized to be associated with the hypercortisolemic state in this case (190). A search for similar defects occurring in the DBD, as well as in the steroid-binding domain of the GR-{alpha} subform and in the splice junction region of the GR, failed to identify mutations in a series of 19 ACTH-secreting tumors, including 2 cases of Nelson’s syndrome, 3 ectopic secretors, and 1 malignant corticotropinoma (192). This suggests that mutations of the GR gene are not commonly involved in the pathogenesis of Cushing’s disease. However, more recently, a study has suggested that deletions of this gene might play a role in the pathogenesis of a number of corticotropinomas: 6 of 22 tumors examined for LOH in 5 known polymorphisms of the gene were found to have monoallelic deletion of GR (193). Because no mutations were found in the remaining GR allele, and no expression studies have been performed in these cases to determine whether GR haploinsufficency was occurring, the functional significance of the deletion of the GR locus in these tumors still remains to be established.

It has also been shown that in vivo models of glucocorticoid resistance, such as a rare type of glucocorticoid-resistant asthma and also the New World primates, appear to be associated with an increase in the expression of GR-ß subform (187, 188, 194). A potential mechanism for the glucocorticoid resistance at the pituitary level observed in corticotroph tumors could be related, therefore, to an altered ratio of the two isoforms of GR, with an excess of GR-ß being potentially able to counteract the activity of the steroid-binding form, GR-{alpha}, or alternatively, actively transrepress glucocorticoid-responsive genes. Relative quantitation of the GR-{alpha} and GR-ß transcription in corticotroph tumors revealed the two isoforms to be expressed at levels similar to those seen in normal pituitary, with a clear predominance of the steroid-binding form over the nonbinding form in all tumors (192). Additionally, while variable levels of expression of the GR-ß subform were observed among the tumors, no correlation with the degree of glucocorticoid resistance, as measured by the response to the high-dose dexamethasone suppression test, was found. Hence, although corticotropinomas show glucocorticoid resistance, this feature cannot be attributed to mutations of critical GR functional domains or abnormal splicing of the GR gene. However, since there has been a report of an apparent lack of correlation between the transcription and posttranslational relative abundance of the GR-{alpha} and GR-ß forms (184), abnormal expression of these two subforms at the posttranslational level, contributing to the glucocorticoid-resistant phenotype in Cushing’s disease, has not been excluded.

3. CRH-R. CRH, also known as CRF, is the main neuroregulator of the HPA axis and plays an important role in coordinating the endocrine, autonomic, and behavioral responses to stress and immune challenge. There are at least two known subforms of CRH-R, types I and II (195, 196, 197, 198, 199, 200, 201, 202). CRH-R type I is predominantly expressed at the pituitary level (200), while type II is more widely expressed throughout the central nervous system and other tissues such as the heart (195). The gene coding for the CRH receptor type I was cloned from a human corticotropic tumor library (200). The cDNA encodes a 415-amino acid protein comprising seven membrane-spanning domains (type Ia). An alternatively spliced form of the receptor, which includes an insert of 29 amino acids in the first intracellular loop, has also been reported (type Ib) (200). Another variant of the human CRH-R has been characterized, which has a 40-amino acid deletion in the amino-terminal domain of the receptor and is the only form of CRH-R detectable in the individual from which it was isolated (203). CRH binds to this variant receptor with lower affinity as compared with the wild-type receptor, and high concentrations of human CRH are required to elevate intracellular cAMP levels in cells transfected with the variant receptor. While the existence of two alternatively spliced transcripts of the CRH-R type II has been reported in the rat, no such variation has yet been characterized in humans (195, 204). The functional significance of the variant transcripts of the CRH type I receptor gene is not fully understood, and their potential role in the regulation of corticotrophs is yet to be established. However, studies in mice have suggested that posttranslational modifications of CRH-R product might occur without corresponding changes in the CRH-R mRNA transcription rate (205).

Recently, increased expression of the CRH-R, without mutations of the coding sequence of the gene, has been reported in corticotroph tumors (206, 207). It is currently unknown whether the up-regulation of the CRH-R1 transcript in corticotroph tumors corresponds to an increased receptor number at the cell surface. If so, this increased transcriptional level of CRH-R1 might reflect an abnormal response of the tumor cells to the CRH stimulus or might solely denote an attempt to counterregulate abnormal processing of the receptor at a posttranslational level (208). A recent study revealed that CRH administration to cultured corticotropinoma cells increased the mRNA levels of CRH-R type I, whereas down-regulation of CRH-R type I was observed with dexamethasone and vasopressin infusion (209). This may be contrasted to the situation in rat anterior pituitary cells, in which CRH administration results in down-regulation of its receptor mRNA (210). Taken together, these findings might explain, in part, the exaggerated ACTH response to CRH injection observed in patients with Cushing’s disease, but not in cured patients or normal individuals, although such responses must also relate to the relative corticosteroid resistance of such tumors.

An important model for Cushing’s disease study is the CRH transgenic mouse, which is discussed in detail later in this review.

4. Nur77. Nur77, also known as NGFI-B (nerve growth factor I-B), a member of the steroid hormone receptor superfamily with no known ligand, is encoded by a growth factor-inducible immediate early gene (211, 212, 213). Nur77 has been proposed to be a mediator of ACTH’s ability to activate the expression of genes that encode steroidogenic enzymes. Since Nur77 is capable of activating such genes as CYP21 (214), it is possible that ACTH induces the synthesis and activity of Nur77, which, in turn, might activate the transcription of steroidogenic enzyme genes. In addition, in vitro studies have suggested that phosphorylation may play an important role in regulating Nur77 function. However, it is still unclear whether this phosphorylation affects Nur77 activity in vivo and how such phosphorylation is regulated by ACTH.

The recent identification of Nur77 as a mediator of the CRH induction of POMC transcription led to the study of the mechanism of glucocorticoid antagonism of receptor activation (215, 216, 217). It has been demonstrated that positive signals mediated by Nur77 (and also probably by related family members), and negative signals exerted by GR, appear to be mechanisms for the control of transcription of both corticotroph and lymphoid cells (218). In agreement with these findings, it has also been demonstrated recently that AtT20 cells transfected with the human Nur77 homolog showed lower glucocorticoid-induced inhibition of POMC mRNA transcription and ACTH secretion (219). Thus, the Nur77-signaling pathway appears to combine stimulatory signals and glucocorticoid repression in both endocrine and lymphoid systems. The role of Nur77 in the corticotroph tumor phenotype has yet to be explored in detail, but the ability to control ACTH and CRH activity renders it a natural candidate for a role in corticotroph cell regulation. For example, overexpression of Nur77 could lead to apparent corticosteroid resistance and a phenotype similar to Cushing’s disease. However, while a transgenic model of Nur77 overexpression is still not available, a Nur77-deficient mouse was not reported to develop pituitary abnormalities (220).

5. Other receptors. GH can be released by stimulation of GH-releasing peptides and their nonpeptide analogs (GHSs) (221). The receptor mediating such signaling has recently been identified (GHS-R) and found to encode a G protein-coupled product distinct from the GH-releasing hormone receptor (222). GHSs induce GH and ACTH secretion in patients with somatotroph and corticotroph tumors, respectively (223, 224). We have recently analyzed a series of 40 pituitary tumors of several lineages for the expression of GHS-R (225): all 8 GH-secreting tumors and 5 of 18 corticotroph tumors (and one ectopic ACTH secretor) were found to express higher transcription levels of GHS-R in comparison with normal pituitaries (Fig. 4Go). In contrast, the majority of the corticotroph tumors, as well as pituitary adenomas arising from other cell types and other neuroendocrine tumors, including ectopic ACTH-secretors, showed lower or equivalent GHS-R transcription levels as compared with normal pituitaries. In addition, some tumor samples, including two corticotroph tumors, had no detectable GHS-R transcripts. While further studies are required to evaluate the biological meaning of GHS-R overexpression in these tumor types, it is possible that this finding helps explain the increased responses to GHS seen in patients with GH- and ACTH-secreting tumors (223, 224).



View larger version (9K):
[in this window]
[in a new window]
 
Figure 4. Relative expression of the GHS-R gene in tissue from 7 normal pituitaries, 8 somatotroph tumors, 4 prolactinomas, 7 nonfunctioning adenomas, 18 corticotroph adenomas, an FSH-oma, and nonpituitary tumors, including 3 ectopic ACTH-secreting tumors (•), 3 insulinomas (*), 1 gastrinoma ({diamondsuit}), and 1 nonsecreting thymic carcinoid tumor ({blacktriangleup}). Open symbols represent samples with no detectable expression under any conditions; solid symbols at the zero GHS-R/GAPDH ratio represent samples with very low levels of GHS-R expression. [Reproduced with permission from M. Korbonits et al.: J Clin Endocrinol Metab 83:3624–3630, 1998 (225 ). © The Endocrine Society.]

 
B. Cytokines and growth factors
The embryological control of pituitary development requires the interaction of several complex mechanisms. The identification of factors involved in such mechanisms may provide insights into the steps leading to differentiation of the pituitary and shed light into disturbances of its normal function that could lead to pituitary tumor growth. Autocrine and paracrine production of cytokines and growth factors has been shown to be involved in the development, function, and cellular organization of the anterior pituitary, in addition to the known classic endocrine regulators. This complex system comprises a multitude of signs that contribute to pituitary homeostasis. Some of the current data on the role of a number of cytokine and growth factors, and the potential implication of this knowledge to the understanding of pituitary tumorigenesis, are briefly discussed.

1. LIF and LIF receptor. LIF is a member of a family of structurally and functionally related cytokines that include interleukin (IL)-6, IL-1, oncostatin M (OSM), and ciliary neurotrophic factor (226). Acting via its own receptor (LIF-R), it induces ACTH secretion and POMC mRNA transcription (5). Although LIF potentiates CRH effects on ACTH, this response occurs via cAMP-independent pathways. Intracellular mediators of LIF include Jak/Trk kinases, p91, and mitogen-activated protein kinases (227). LIF has been found to be expressed in the developing human fetal pituitary and in both normal and tumorous adult pituitary tissue (5). More recent studies performed in murine AtT20 cells have indicated that LIF reduces proliferation, induces ACTH secretion, and potentiates the effects of CRH on ACTH secretion while suppressing the mitotic effects of CRH, suggesting its role as a differentiation factor for the corticotroph (228). Furthermore, there is evidence to suggest that LIF inhibits pituitary angiogenesis (229, 230) which, in addition to its expression in pituitary tumors and its potential antiproliferative effect in corticotrophs, might implicate this factor in pituitary tumorigenesis. In keeping with the presumed functions of LIF from previous in vivo studies, low levels of ACTH were found to be a prominent feature of LIF knockout mice (231). However, transgenic mice with overexpressed LIF, under regulation of the rat GH promoter, show arrested pituitary maturation, invagination of Rathke’s cleft predisposing to cyst formation, marked GH deficiency, and an increased mass of ACTH-secreting cells without a corresponding change in POMC mRNA transcription (232). The expected antiproliferative effects of LIF on corticotrophs anticipated by the studies in AtT20 cells (228) were not seen clearly in the transgenic model. The reasons for this apparent discordance between the antimitotic effects of LIF in corticotroph cells in previous studies and the corticotroph hyperplasia observed in the transgenic animals are not clear. It is possible that the effects of LIF on specific pituitary cell types may vary cyclically according to different phases of embryonic development, a phenomenon that would not be reproduced by this transgenic model. In fact, a recently reported transgenic mouse in which LIF expression was driven by the {alpha}-GSU promoter was shown to exhibit corticotroph hyperplasia and cushingoid features, as well as reduced gonadotroph, somatotroph, and lactotroph function (233). Also, LIF has been seen to influence the development of ciliated epithelium. Certain differences seen between the phenotypes of the two transgenic mice are possibly attributed to cell-specific expression, time of LIF expression relative to embryonic development, and level of LIF expression in each one of the models. Further studies designed to determine the specific role of LIF in corticotroph tumors are needed to help clarify its contribution to pituitary tumorigenesis.

2. Epidermal growth factor (EGF) and EGF receptor (EGF-R). Some studies have suggested a potential role for EGF in stimulating corticotroph proliferation and ACTH secretion in vitro (234). However, these effects may have been secondary to the ability of EGF to stimulate CRH synthesis (235). A series of pituitary tumors was investigated in relation to the immunohistochemical expression of EGF and EGF-R (236): expression of both products was found in all normal pituitaries tested and in 60% of corticotroph adenomas, whereas it was less frequent in other tumor cell lineages. Another study detected EGF and EGF-R expression in all types of human pituitary adenomas, albeit at variable levels (237). Conversely, lack of both EGF and EGF-R expression in corticotroph adenomas has been noted in another study (238). In the light of these controversial results, it is not clear whether these products play any role in pituitary oncogenesis.

3. Other cytokines and growth factors. Although many cytokines and growth factors mediate cell division, there has been no clear evidence so far for a prominent role of any cytokine in the development of pituitary tumors. More important effects of these substances are indicated by their critical role in regulating specific pituitary hormone regulation (239). The best studied conditions of cytokine hyperactivation in animal models are those in which the effects of transforming growth factor-{alpha} (TGF-{alpha}) and nerve growth factor (NGF) have been analyzed. However, overexpression of both genes has been associated with lactotroph cell proliferation (240, 241).

IL-6 is a known potent ACTH secretagogue; however, its effect on cell division is less clear. Opposing results have been observed in studies using different cell models with regard to the ability of IL-6 to induce cell proliferation (242).

FGF-4 has been shown to be expressed only in neoplastic tissue in the adult pituitary. However, the potent mitogenic effects of FGF-4 have been characterized only in PRL-secreting cells (243).

Galanin, a peptide retaining little homology with other neuropeptides, has been detected by immunostaining in normal pituitary and more prominently in corticotroph tumors, whereas it was less reactive in other tumor types (244). In vivo studies, on the other hand, have implicated galanin predominantly in GH and PRL regulation (245). Galanin appears to mediate estrogen-stimulated lactotroph hyperplasia, which may implicate this peptide in prolactinoma development (245), but less is known about its role in corticotroph regulation.

TGF-ß, unlike TGF-{alpha}, has been suggested to act as an inhibitor of tumor cell proliferation, due to its effects on p21, p27, and p15 induction (246). Interestingly, human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-ß receptor II gene (TGF-ßR-II) (247). By inducing the escape of cells from TGF-ß-mediated growth control, TGF-ß-R-II mutations link DNA repair defects with a specific pathway of tumor progression. Such an association has not yet been explored in pituitary tumors.

These studies indicate that, with the possible exception of LIF, which has yet to be further characterized in terms of its regulation of corticotroph growth and differentiation, no other cytokine or growth factor has been demonstrated to play a major part in corticotroph tumorigenesis. It is possible that these substances may exert a regulatory influence on an already altered pituitary cell or preestablished clonal structure, contributing to tumor development, rather than being the primary initiator(s) of tumoral formation.

C. Developmental genes
The essential roles of homeodomain proteins in cell fate determination during development have been demonstrated in organisms as divergent as Drosophila and higher mammals (248). The genes involved in the differentiation of the embryonic pituitary are important in determining the degree of specialization of each cell lineage, but little is known about the ontogeny of the human corticotroph. Immunoreactive ACTH is already detected in Rathke’s pouch at the fifth gestational week, while a more mature hypophyseal-portal system only occurs between weeks 8 and 14 (1). Because the fetal corticotroph is sensitive to CRH only after week 14, other factors are believed to be involved in the specificity of the corticotroph in earlier weeks (249, 250, 251). Commitment to developing a distinct pituitary gland occurs when the rudimentary Rathke’s pouch, which represents the primordium of the anterior and intermediate lobes, comes into contact with ventral hypothalamus, of neuroectodermal origin. From this point on, the Rathke’s epithelium starts to differentiate into pituitary-specific cell lineages (1, 2). A knockout model has been developed in mice where the homeobox gene Lhx3 (also known as mLim-3 and P-Lim) was targeted (3). Homozygous null mice formed Rathke’s pouch, but no anterior or intermediate pituitary lobes developed. The growth arrest observed in the Rathke’s pouch was shown to be caused by a failure in proliferation rather than increased apoptosis. All cell lineages were affected, except for the corticotrophs, indicating that these cells are regulated by a factor or factors that are distinct from the remaining pituitary cells very early in the development, possibly before the activation of {alpha}-glycoprotein subunit primitive cells (3). Although POMC expression was detected in some corticotroph cells, these failed to proliferate, indicating a potential role for Lhx3 product in the growth of both differentiated and undifferentiated pituitary cells (3). Alternatively, it could indicate its role in providing pituitary cells with trophic factors from adjacent structures such as the hypothalamus or mesenchyme. Recent studies in AtT20 cells have demonstrated that Lhx3 may play a key role in inducing PRL gene expression in lactotrophs independently of the Pit-1/GHF-1 pathway (252). The Lhx3 knockout is therefore an invaluable tool for studying early development of the pituitary and might also provide clues on the role of proliferation-inducing factors in the progress and development of pituitary tumors. However, as the human homologue of Lhx3 has not as yet been characterized, the specific role of this gene in humans remains speculative.

1. PTX gene family. Ptx1 (also known as Otx-1) is a member of the small bicoid family of homeobox-containing genes (4, 253). It was isolated as a tissue-restricted transcription factor of the POMC gene. The pattern of Ptx1 expression supports the hypothesis that Ptx1 defines a primordial structure that may be involved in the commitment to the corticotroph phenotype (4, 254). Two highly homologous subforms of Ptx1, Ptx1a and Ptx1b, have now been identified, and they both appear to specifically regulate genes expressed exclusively at the pituitary level, including POMC (255). Interestingly, Ptx1a appears to be critical to the expression of the {alpha}-subunit of glycoprotein hormones (256).

Another homeobox gene involved in the pathogenesis of the Rieger syndrome, RIEG1, and its mouse homologue, Rieg1 (also known as Ptx2), have been recently identified by positional cloning and found to be highly homologous to the Ptx1 gene product (257). Ptx2 gene produces two alternatively spliced mRNA transcripts, which encode proteins of 271 (Ptx2a) and 317 amino acids (Ptx2b), respectively. Ptx2 is expressed in both developing and adult pituitary gland, eye, and brain tissues, suggesting an important role in development and maintenance of anterior structures. Ptx2 was mapped close to EGF on mouse chromosome 3, in a region having extensive syntenic homology with human chromosome 4q. Mutations of the human RIEG1 gene have been identified in the Rieger syndrome, an autosomal-dominant disorder with variable craniofacial, dental, eye, and pituitary anomalies (258, 259).

Another new murine gene, Ptx3, was isolated that encodes a homeoprotein with strong homology to the other Ptx proteins, which may suggest that this is a third member of the family (260). However, the embryological expression pattern of Ptx3 was much more restricted than the remaining isoforms: only the developing lens appears to express the Ptx3 transcript (260).

The potential role of the Ptx genes in mouse pituitary tumorigenesis has not yet been explored, but their important role in embryological pituitary development (in particular, Ptx1 and Ptx2) makes these genes natural candidates for an involvement in pituitary growth abnormalities. The full characterization of the human homologs of the Ptx family of genes will shed some light into their actions involving pituitary regulation. A potential role for homeobox genes in human malignancies has already been suggested (261, 262), as well as their interaction with cytokines such as TGF (259). Studies investigating the potential role of Ptx genes in pituitary tumor formation might provide clues as to the involvement of homeobox genes in tumor pathogenesis.

2. POU factors. Specific families of transcription factors mediate events in the sequential maturation of distinct cell phenotypes (263, 264). POU is a family of transcription factors that specifically recognizes two classes of cis-acting regulatory elements that bear little sequence similarity, the octamer motif ATGCAAAT and the TAATGARAT motif (265, 266). The most well known of these factors is possibly the Pit1 product, which has been shown to be related to the embryological development of the somatotroph, mammotroph, and thyrotroph lineages (1). Members of the class IV POU domain transcription factor Brn-3a (also known as Brn3.0) and two highly related factors, Brn-3b and Brn-3c, are differentially expressed in the developing and mature mammalian nervous system (266, 267). While Brn-3a and Brn-3c products activate their target genes, Brn-3b has repressor activities that can occasionally interfere with activation by Brn-3a or c (268). Analysis of mice null for the Brn-3a locus shows that Brn-3a is required for the survival of subpopulations of proprioceptive, mechanoceptive, and nociceptive sensory neurons (269). Targeted deletion of Brn-3a also alters differentiation, migration, or survival of specific neuronal populations, resulting in defective suckling and in uncoordinated limb and trunk movements, ultimately leading to early postnatal death. No abnormalities have been reported at the pituitary level. Thus, Brn-3a exerts its major developmental effects in somatosensory neurons and in brainstem nuclei involved in motor control (263, 270, 271).

Brn-3a has been found to stimulate POMC transcription and also to exert mitogenic effects on targeted cells when cotransfected with H-RAS (268). Furthermore, Brn3a has been suggested to act as a potential oncogene in neuroectodermal tumors (268). A recent study examining the levels of Brn3a in a series of pituitary and ectopic tumors secreting ACTH reported a high expression of this factor to be associated with more aggressive forms of ACTH-secreting tumors, both of pituitary and nonpituitary origin, but no correlation was seen with POMC expression in such tumors (272). It appears that while Brn3a induces POMC transcription, its potential association with corticotroph tumor aggressiveness is not dependent on this activation. It is believed that activation of the POMC promoter requires that various factors interact synergistically (273). It appears from the study on ACTH-secreting tumors that Brn3a is not necessary for POMC transcription, as the majority of pituitary corticotroph tumors had levels of Brn3a similar to GH- and PRL-secreting tumors. However, a clearer inverse correlation was seen between the degree of tumor differentiation and the levels of Brn3a among the ectopic ACTH secretors (272). Analysis of Brn3a in other tumor types will determine whether its correlation with more aggressive tumor forms is also observed and will shed light on the mechanisms accounting for such an association.


    V. Miscellaneous
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 
A. Other genes
Other genes such as the retinoid X receptor, involved in the regulation of growth and differentiation, the apoptosis inhibitors such as the BCL2 gene, and others have been examined for their role in pituitary tumorigenesis (274, 275). While some abnormalities have been found in a number of tumors, it is not clear whether the defects observed are specific to the pituitary tumorous phenotype or whether they represent a general phenomenon related to neoplastic transformation. If specific, it remains unclear whether the finding represents the original cause, or whether it is simply an effect of another, still unknown, primary abnormality.

B. Methylation
It has been generally accepted that an important mechanism of gene inactivation in mammals is methylation (276, 277, 278). In general, it is found that the promoters of expressed genes are unmethylated, whereas those of genes that are not expressed are methylated (279). Unmethylated CpG islands located in gene promoter regions are a principal target of hypermethylation. This hypermethylation correlates with transcriptional repression in a similar manner to the effect of inactivating mutations of tumor suppressor genes (277, 278, 280, 281, 282, 283). A tumorigenesis model attempting to reconcile the role of the nonspecific phenomenon of methylation and more gene- and/or tissue-specific alterations has been proposed (280). According to this model, tumor progression results from an initial clonal expansion of heterogeneous cell populations directed by continuous interaction between methylation abnormalities and classic genetic events.

Pituitary tumor cells have been found to be targets of abnormal methylation: as noted above, the p16 gene has been found to be transcriptionally silenced due to hypermethylation of its promoter in the majority of pituitary adenomas examined (75). Recently, it has been found that the specific "pituitary" POMC promoter (the promoter that drives the transcription of the translated POMC peptide, as opposed to an alternative promoter that leads to the transcription of a nonsecreted peptide) is unmethylated in all POMC-expressing tissues and cells and is methylated in nonexpressing tissues (284). In addition, the activity of the promoter was lost by in vitro methylation in the POMC-secreting small-cell lung cancer cell line DMS-79. The alternative promoter was found to be methylated in all tissues. In ectopic ACTH-secreting tumors, the "pituitary" promoter was found to be specifically unmethylated, while the alternative promoter was methylated, suggesting that this regulation is not a random process and might be related to tumorigenesis in these cells. It is possible that the expression of the POMC promoter confers some growth or survival advantage to certain cell types, such as DMS-79 cells. Forthcoming studies might reveal the role of POMC regulation in pituitary tumors and shed some light into the mechanisms regulating methylation in a tissue-specific manner.


    VI. Perspectives: Old and New Tools for Understanding Pituitary Pathogenesis
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 
A. Transgenic/knockout mice models
The epidemiology of cancer in humans and in animals suggests that multiple genetic events are responsible for the genesis of malignant tumors. During the development of many tumors, distinctive changes can be recognized: normal unaffected tissue, hyperplasia with a high incidence of proliferating cells, induction of tumor angiogenesis with the new growth of capillaries, solid tumor formation (neoplasia), and finally, metastasis. The molecular analysis of tumorigenesis is often restricted by the lack of availability of tissue specimens from the multiple stages. For this reason, the genetic reproducibility and the accessibility of tissue specimens have made transgenic mice an important tool in the study of the molecular events that are involved in the multistep progression to the tumor phenotype.

Many transgenic mouse models of human cancer exhibit similar patterns of stepwise tumor development (285). However, there are many other models in which an obvious parallel with the corresponding human disease system is not observed. We have referred to some of these examples earlier when the RB1 and p27KIP1 null mice were mentioned (48, 59, 77, 78, 79, 286). The reasons for the lack of correspondence between the murine and human models is not entirely understood, but differences in the regulatory mechanisms involved in certain redundant systems, as well as the involvement of modulating factors contributing to the final phenotype, might play a role in this distinction. In addition, variations of the genetic background of the mice used to create specific disease models might contribute to differences in the phenotype resulting from such systems. It is possible that specific strains of animals produce distinct phenotypes when the same genomic manipulation is performed. Nevertheless, despite the obvious limitations and drawbacks represented by these models of study, as stated above, transgenic/knockout models are still considered invaluable tools for the understanding of in vivo effects of specific gene alterations. Important advances into the mechanisms involved in HPA axis regulation have been provided by animal models of excess or null CRH expression.

A transgenic mouse model overexpressing the CRH gene driven by a metallothionein promoter showed many features characteristic of Cushing’s disease, which were mostly reversed by adrenalectomy (287). Compared with endogenous CRH tissue distribution, the transgenic animals showed a broader CRH expression in the brain, possibly due to a less efficient glucocorticoid-mediated CRH down-regulation in these tissues. Transgenic mice were also noted to exhibit an anxiogenic-like state, similar to the behavior assumed by animals under chronic stress (288). Furthermore, an impaired immune response, related to both quantitative and qualitative B cell activity, was observed in the transgenic mice. Both endocrine and behavioral features of these animals were counteracted by injection of the CRH antagonist, {alpha}-helical CRH(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41), indicating that the effects observed were specifically caused by the excess of CRH. However, despite the fact that high levels of CRH produced a hypercortisolemic state with features suggestive of Cushing’s disease, no tumors were seen in the mice pituitary corticotrophs. It remains to be established whether chronic corticotroph hyperplasia in humans facilitate the development of a functioning corticotroph adenoma.

Targeted disruption of CRH, CRH-R1, and GR genes in mice have also provided important insights into the mechanisms involved in HPA axis regulation at all stages of animal development. The gene-deficiency model helps delineate not only the specific role of a certain product from the phenotype of its absence, but also provides clues as to the compensatory mechanisms that are activated or arise when it is not present. These compensatory systems, in turn, may shed light on novel pathways that might play a critical role in the maintenance of homeostasis and might therefore contribute to the understanding of tumorigenesis in such systems. All such models have contributed to a better knowledge of the pathways involving HPA axis regulation, emphasizing the specific role for each particular product. These three knockout models have revealed phenotypes that share many common features. Mice heterozygous for CRH deficiency were fertile and did not have any abnormal phenotype (289); their offspring included homozygously deficient mice in a Mendelian-type ratio that developed severe glucocorticoid deficiency. However, normal AVP, ACTH, and POMC activities in these mice indicate that CRH is not essential for corticotroph differentiation during development. These studies also demonstrated the essential role of CRH in stimulating the adrenal production of corticosteroids, which is not fully compensated for by other ACTH secretagogues. Another intriguing system for studying HPA axis regulation is the CRH-R1 knockout mouse model: almost 30% of the mice homozygous for the mutation were not viable. However, those that survived were fertile but showed markedly reduced stress-induced ACTH and corticosterone responsiveness (290, 291). In addition, atrophy of the adrenal medulla was observed, with maintenance of the integrity of the cortical layers. This atrophy was rescued by administration of ACTH (290). Pituitary corticotrophs were normal in size and number. The knockout animals exhibited reduced anxiety-related behavior. The offspring of homozygotes died within 48 h after birth with marked lung dysplasia similar to that seen in the offspring of CRH-null animals. GR-null mice also represent important models for understanding HPA axis regulation. Most of the mice with a disrupted GR gene died soon after birth due to severe lung atelectasis; perinatal induction of gluconeogenic enzymes in the liver was impaired; feedback control of glucocorticoid synthesis via the HPA axis was also found to be markedly impaired leading to increased plasma levels of corticosterone and ACTH. Extensive hypertrophy and hyperplasia of the cortical zones of the adrenal and induction of genes involved in steroid biosynthesis were observed in the GR-null mice, whereas the adrenal medulla was atrophic, in a manner similar to that reported in the CRH-R1-null mice. These knockout animals continue to provide valuable tools for studies on interactive functions and detailed characterization of specific pathways as yet unexplored.


    VII. Conclusions
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 
While much has been learned in purely descriptive terms regarding the etiology of corticotropinomas, there are still more questions than answers. The speed of scientific advance in the field of molecular biology is expected to change this situation over the next few years. Currently, it would appear that most of the oncogenes and tumor suppressor genes implicated in nonpituitary cancers are not commonly involved in corticotroph tumors, although there is evidence for the involvement of tumor supressor gene products such as p27 in the progression from adenomatous to more aggressive phenotypes (see Table 2Go). As the corticotroph tumor usually does not carry many gross histological differences as compared with the normal corticotroph tissue, it seems most likely that derangements of specific corticotroph-regulatory pathways might be disrupted. Several studies have investigated the most obvious candidate genes, particularly the primary stimulatory and inhibitory receptors, without any clear evidence in favor of a common defect. It is our speculation that there are probably mutations of the specific corticotroph-regulatory pathways leading to relative feedback insensitivity. Thus, a mutational abnormality, possibly on the background of preexisting proliferative signals, might give rise to a group of cells that are relatively resistant to feedback effects and thus are being reset to a higher level of cortisol in relation to ACTH. The surrounding normal corticotrophs would show secretory and growth suppression in response to the higher prevailing level of cortisol, thus providing the clone with a growth advantage. This small benign adenoma may, in certain cases, accumulate further "hits" in less specific oncogenes or tumor suppressor genes, leading to increased invasiveness and possible carcinomatous transformation. It is hoped that in the near future, with the identification of novel molecular pathways, it will be possible to understand the molecular mechanisms involved in the pathogenesis of Cushing’s disease. Future studies are also expected to provide tools to a better prediction of tumor behavior and may eventually provide new insights that might contribute to the development of novel molecular targets for therapy.


View this table:
[in this window]
[in a new window]
 
Table 2. Genes implicated in pituitary tumor aggressiveness according to their putative general mechanism of action (see text)

 


    Acknowledgments
 
Charis Eng is acknowledged for her support.


    Footnotes
 
Address reprint requests to: Professor A. B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom.

1 Recipient of a Susan G. Komen Breast Cancer Foundation grant. Current address: Translational Research Laboratory, Human Cancer Genetics Unit, Adult Oncology Department, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115-6084 USA. Back


    References
 Top
 Abstract
 I. Introduction
 II. Protooncogenes
 III. Tumor Suppressor Genes
 IV. Specific Genes
 V. Miscellaneous
 VI. Perspectives: Old and...
 VII. Conclusions
 References
 

  1. 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]
  2. Rhodes SJ, DiMattia GE, Rosenfeld MG 1994 Transcriptional mechanisms in anterior pituitary cell differentiation. Curr Opin Genet Dev 4:709–717[CrossRef][Medline]
  3. Sheng HZ, Zhadanov AB, Mosinger Jr B, Fujii T, Bertuzzi S, Grinberg A, Lee EJ, Huang SP, Mahon KA, Westphal H 1996 Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science 272:1004–1007[Abstract]
  4. Lamonerie T, Tremblay JJ, Lanctot C, Therrien M, Gauthier Y, Drouin J 1996 Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev 10:1284–1295[Abstract/Free Full Text]
  5. Akita S, Webster J, Ren SG, Takino H, Said J, Zand O, Melmed S 1995 Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion. J Clin Invest 95:1288–1298
  6. Grossman A 1992 What is the cause of Cushing’s disease? Clin Endocrinol (Oxf) 36:451–452[Medline]
  7. Hunder GG 1966 Pathogenesis of Cushing’s disease. Mayo Clin Proc 41:29–39[Medline]
  8. Tsigos C, Chrousos GP 1996 Differential diagnosis and management of Cushing’s syndrome. Annu Rev Med 47:443–461[CrossRef][Medline]
  9. Krieger DT 1983 Physiopathology of Cushing’s disease. Endocr Rev 4:22–43[Abstract/Free Full Text]
  10. Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S 1990 Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 71:1427–1433[Abstract/Free Full Text]
  11. Alexander JM, Biller BM, Bikkal H, Zervas NT, Arnold A, Klibanski A 1990 Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Invest 86:336–340
  12. Jacoby LB, Hedley-Whyte ET, Pulaski K, Seizinger BR, Martuza RL 1990 Clonal origin of pituitary adenomas. J Neurosurg 73:731–735[Medline]
  13. Schulte HM, Oldfield EH, Allolio B, Katz DA, Berkman RA, Ali IU 1991 Clonal composition of pituitary adenomas in patients with Cushing’s disease: determination by X-chromosome inactivation analysis. J Clin Endocrinol Metab 73:1302–1308[Abstract/Free Full Text]
  14. Vogelstein B, Fearon ER, Hamilton SR, Preisinger AC, Willard HF, Michelson AM, Riggs AD, Orkin SH 1987 Clonal analysis using recombinant DNA probes from the X-chromosome. Cancer Res 47:4806–4813[Abstract/Free Full Text]
  15. Mashal RD, Lester SC, Sklar J 1993 Clonal analysis by study of X-chromosome inactivation in formalin-fixed paraffin-embedded tissue. Cancer Res 53:4676–4679[Abstract/Free Full Text]
  16. Thomas GA, Williams D, Williams ED 1988 The demonstration of tissue clonality by X-linked enzyme histochemistry. J Pathol 155:101–108[CrossRef][Medline]
  17. Prchal JT, Prchal JF, Belickova M, Chen S, Guan Y, Gartland GL, Cooper MD 1996 Clonal stability of blood cell lineages indicated by X-chromosomal transcriptional polymorphism. J Exp Med 183:561–567[Abstract/Free Full Text]
  18. Alvaro V, Levy L, Dubray C, Roche A, Peillon F, Querat B, Joubert D 1993 Invasive human pituitary tumors express a point-mutated {alpha}-protein kinase-C. J Clin Endocrinol Metab 77:1125–1129[Abstract]
  19. Ezzat S, Zheng L, Smyth HS, Asa SL 1997 The c-erbB-2/neu proto-oncogene in human pituitary tumours. Clin Endocrinol (Oxf) 46:599–606[CrossRef][Medline]
  20. Pei L, Melmed S, Scheithauer B, Kovacs K, Prager D 1994 H-ras mutations in human pituitary carcinoma metastases. J Clin Endocrinol Metab 78:842–846[Abstract]
  21. Ikeda H, Yoshimoto T 1992 The relationship between c-myc protein expression, the bromodeoxyuridine labeling index and the biological behavior of pituitary adenomas. Acta Neuropathol (Berl) 83:361–364[CrossRef][Medline]
  22. Komminoth P, Roth J, Muletta-Feurer S, Saremaslani P, Seelentag WK, Heitz PU 1996 RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab 81:2041–2046[Abstract]
  23. Boggild MD, Jenkinson S, Pistorello M, Boscaro M, Scanarini M, McTernan P, Perrett CW, Thakker RV, Clayton RN 1994 Molecular genetic studies of sporadic pituitary tumors. J Clin Endocrinol Metab 78:387–392[Abstract]
  24. Williamson EA, Ince PG, Harrison D, Kendall-Taylor P, Harris PE 1995 G-protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas. Eur J Clin Invest 25:128–131[Medline]
  25. Oyesiku NM, Evans CO, Brown MR, Blevins LS, Tindall GT, Parks JS 1997 Pituitary adenomas: screening for G{alpha}q mutations. J Clin Endocrinol Metab 82:4184–4188[Abstract/Free Full Text]
  26. Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L 1989 GTPase inhibiting mutations activate the {alpha} chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340:692–696[CrossRef][Medline]
  27. Pei L, Melmed S 1997 Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol 11:433–441[Abstract/Free Full Text]
  28. Zhang X, Horwitz GA, Prezant TR, Valentini A, Nakashima M, Bronstein MD, Melmed S 1999 Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol Endocrinol 13:156–166[Abstract/Free Full Text]
  29. Dominguez A, Ramos-Morales F, Romero F, Rios RM, Dreyfus F, Tortolero M, Pintor-Toro JA 1998 hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms. Evidence for a transcriptional activation function of hPTTG. Oncogene 17:2187–2193[CrossRef][Medline]
  30. Hollstein M, Sidransky D, Vogelstein B, Harris CC 1991 p53 mutations in human cancers. Science 253:49–53[Abstract/Free Full Text]
  31. Levine AJ 1990 Tumor suppressor genes. Bioessays 12:60–66[CrossRef][Medline]
  32. Hinds P, Finlay C, Levine AJ 1989 Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J Virol 63:739–746[Abstract/Free Full Text]
  33. McBride OW, Merry D, Givol D 1986 The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci USA 83:130–134[Abstract/Free Full Text]
  34. Benchimol S, Lamb P, Crawford LV, Sheer D, Shows TB, Bruns GA, Peacock J 1985 Transformation associated p53 protein is encoded by a gene on human chromosome 17. Somat Cell Mol Genet 11:505–510[CrossRef][Medline]
  35. Wolf D, Harris N, Rotter V 1984 Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. Cell 38:119–126[CrossRef][Medline]
  36. Zakut-Houri R, Bienz-Tadmor B, Givol D, Oren M 1985 Human p53 cellular tumor antigen: cDNA sequence and expression in COS cells. EMBO J 4:1251–1255[Medline]
  37. Matlashewski G, Lamb P, Pim D, Peacock J, Crawford L, Benchimol S 1984 Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene. EMBO J 3:3257–3262[Medline]
  38. Wolf D, Laver-Rudich Z, Rotter V 1985 In vitro expression of human p53 cDNA clones and characterization of the cloned human p53 gene. Mol Cell Biol 5:1887–1893[Abstract/Free Full Text]
  39. Caron de Fromentel C, Soussi T 1992 TP53 tumor suppressor gene: a model for investigating human mutagenesis. Genes Chromosomes Cancer 4:1–15[Medline]
  40. Buckley N, Bates AS, Broome JC, Strange RC, Perrett CW, Burke CW, Clayton RN 1995 p53 Protein accumulates in Cushings adenomas and invasive nonfunctional adenomas. J Clin Endocrinol Metab 80:692–696
  41. Herman V, Drazin NZ, Gonsky R, Melmed S 1993 Molecular screening of pituitary adenomas for gene mutations and rearrangements. J Clin Endocrinol Metab 77:50–55[Abstract]
  42. Levy A, Hall L, Yeudall WA, Lightman SL 1994 p53 Gene mutations in pituitary adenomas: rare events. Clin Endocrinol (Oxf) 41:809–814[Medline]
  43. Piette J, Neel H, Marechal V 1997 Mdm2: keeping p53 under control. Oncogene 15:1001–1010[CrossRef][Medline]
  44. Momand J, Zambetti GP 1997 Mdm-2: "big brother" of p53. J Cell Biochem 64:343–352[CrossRef][Medline]
  45. Oren M 1997 Lonely no more: p53 finds its kin in a tumor suppressor haven. Cell 90:829–832[CrossRef][Medline]
  46. Dickman S 1997 First p53 relative may be a new tumor suppressor. Science 277:1605–1606[Free Full Text]
  47. Clurman B, Groudine M 1997 Tumour-suppressor genes. Killer in search of a motive? Nature 389:122–123[CrossRef][Medline]
  48. Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F, Caput D 1997 Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90:809–819[CrossRef][Medline]
  49. Jost CA, Marin MC, Kaelin Jr WG 1997 p73 Is a human p53-related protein that can induce apoptosis. Nature 389:191–194[CrossRef][Medline]
  50. Garkavtsev I, Grigorian IA, Ossovskaya VS, Chernov MV, Chumakov PM, Gudkov AV 1998 The candidate tumour suppressor p33ING1 cooperates with p53 in cell growth control. Nature 391:295–298[CrossRef][Medline]
  51. Senoo M, Seki N, Ohira M, Sugano S, Watanabe M, Tachibana M, Tanaka T, Shinkai Y, Kato H 1998 A second p53-related protein, p73L, with high homology to p73. Biochem Biophys Res Commun 248:603–607[CrossRef][Medline]
  52. Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M, Ikawa S 1998 Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nat Med 4:839–843[CrossRef][Medline]
  53. Schmale H, Bamberger C 1997 A novel protein with strong homology to the tumor suppressor p53. Oncogene 15:1363–1367[CrossRef][Medline]
  54. Zou MJ, Shi YF, Farid NR 1994 Frequent inactivation of the retinoblastoma gene in human thyroid carcinomas. Endocrine J 2:193–198
  55. Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EYHP 1987 Human retinoblastoma susceptibility gene: cloning, identification and sequence. Science 235:1394–1399[Abstract/Free Full Text]
  56. Toguchida J, McGee TL, Paterson JC, Eagle JC, Tucker S, Yandell DW, Dryja TP 1994 Human retinoblastoma susceptiblity gene. Genomics 17:535–543
  57. Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD 1988 Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241:353–357[Abstract/Free Full Text]
  58. Sakai T, Ohtani N, McGee TL, Robbins PD, Dryja TP 1991 Oncogenic germ-line mutations in Sp1 and ATF sites in the human retinoblastoma gene. Nature 353:83–86[CrossRef][Medline]
  59. Hu N, Gutsmann A, Herbert DC, Bradley A, Lee WH, Lee EY 1994 Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9:1021–1027[Medline]
  60. Harvey M, Vogel H, Lee EY, Bradley A, Donehower LA 1995 Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res 55:1146–1151[Abstract/Free Full Text]
  61. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA 1992 Effects of an Rb mutation in the mouse. Nature 359:295–300[CrossRef][Medline]
  62. Cryns VL, Alexander JM, Klibanski A, Arnold A 1993 The retinoblastoma gene in human pituitary tumors. J Clin Endocrinol Metab 77:644–646[Abstract]
  63. Melmed S 1994 Pituitary neoplasia. Endocrinol Metab Clin North Am 23:81–92[Medline]
  64. Woloschak M, Roberts JL, Post KD 1994 Loss of heterozygosity at the retinoblastoma locus in human pituitary tumors. Cancer 74:693–696[CrossRef][Medline]
  65. Pei L, Melmed S, Scheithauer B, Kovacs K, Benedict WF, Prager D 1995 Frequent loss of heterozygosity at the retinoblastoma susceptibility gene (RB) locus in aggressive pituitary tumors: evidence for a chromosome 13 tumor suppressor gene other than RB. Cancer Res 55:1613–1616[Abstract/Free Full Text]
  66. Pearce SH, Trump D, Wooding C, Sheppard MN, Clayton RN, Thakker RV 1996 Loss of heterozygosity studies at the retinoblastoma and breast cancer susceptibility (BRCA2) loci in pituitary, parathyroid, pancreatic and carcinoid tumours. Clin Endocrinol (Oxf) 45:195–200[CrossRef][Medline]
  67. Hatta Y, Hirama T, Takeuchi S, Lee E, Pham E, Miller CW, Strohmeyer T, Wilczynski SP, Melmed S, Koeffler HP 1995 Alterations of the p16 (MTS1) gene in testicular, ovarian, and endometrial malignancies. J Urol 154:1954–1957[CrossRef][Medline]
  68. Lees E 1995 Cyclin dependent kinase regulation. Curr Opin Cell Biol 7:773–780[CrossRef][Medline]
  69. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA 1994 Deletions of the cyclin-dependent kinase 4 inhibitor in multiple human cancers. Nature 368:753–756[CrossRef][Medline]
  70. Nigg EA 1995 Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. Bioessays 17:471–480[CrossRef][Medline]
  71. Sherr CJ 1995 D-type cyclins. Trends Biochem Sci 20:187–190[CrossRef][Medline]
  72. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ 1993 Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 7:331–342[Free Full Text]
  73. Shapiro GI, Edwards CD, Kobzik L, Godleski J, Richards W, Sugarbaker DJ, Rollins BJ 1995 Reciprocal RB inactivation and P16(Ink4) expression in primary lung cancers and cell lines. Cancer Res. 55:505–509
  74. Woloschak M, Yu A, Xiao J, Post KD 1996 Frequent loss of the P16INK4a gene product in human pituitary tumors. Cancer Res 56:2493–2496[Abstract/Free Full Text]
  75. Woloschak M, Yu A, Post KD 1997 Frequent inactivation of the p16 gene in human pituitary tumors by gene methylation. Mol Carcinog 19:221–224[CrossRef][Medline]
  76. Farrell WE, Simpson DJ, Bicknell JE, Talbot AJ, Bates AS, Clayton RN 1997 Chromosome 9p deletions in invasive and noninvasive nonfunctional pituitary adenomas: the deleted region involves markers outside of the MTS1 and MTS2 genes. Cancer Res 57:2703–2709[Abstract/Free Full Text]
  77. Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM 1996 A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85:733–744[CrossRef][Medline]
  78. Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A 1996 Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85:721–732[CrossRef][Medline]
  79. Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K 1996 Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85:707–720[CrossRef][Medline]
  80. Elledge SJ 1996 Cell cycle checkpoints: preventing an identity crisis. Science 274:1664–1672[Abstract/Free Full Text]
  81. Kaufmann WK, Paules RS 1996 DNA damage and cell cycle checkpoints. FASEB J 10:238–247[Abstract]
  82. Weinert T, Lydall D 1993 Cell cycle checkpoints, genetic instability and cancer. Semin Cancer Biol 4:129–140[Medline]
  83. Murray AW 1995 The genetics of cell cycle checkpoints. Curr Opin Genet Dev 5:5–11[CrossRef][Medline]
  84. Hartwell L, Weinert T, Kadyk L, Garvik B 1994 Cell cycle checkpoints, genomic integrity, and cancer. Cold Spring Harb Symp Quant Biol 59:259–263[Abstract/Free Full Text]
  85. Kato JY, Matsuoka M, Polyak K, Massague J, Sherr CJ 1994 Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell 79:487–496[CrossRef][Medline]
  86. Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J 1994 Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78:59–66[CrossRef][Medline]
  87. Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A 1994 p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-ß and contact inhibition to cell cycle arrest. Genes Dev 8:9–22[Abstract/Free Full Text]
  88. Dahia PLM, Aguiar RCT, Honegger J, Fahlbush R, Jordan S, Lowe DG, Lu X, Besser GM, Grossman AB 1998 Mutation and expression analysis of the p27/kip1 gene in corticotropin-secreting tumours. Oncogene 16:69–76[CrossRef][Medline]
  89. Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM, Barnes DM, Shousha S, O’Hare MJ, Lu X 1997 High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci USA 94:6380–6385[Abstract/Free Full Text]
  90. Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, Daling JR, Roberts JM 1997 Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 3:222–225[CrossRef][Medline]
  91. Tan P, Cady B, Wanner M, Worland P, Cukor B, Magi-Galluzzi C, Lavin P, Draetta G, Pagano M, Loda M 1997 The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a, b) invasive breast carcinomas. Cancer Res 57:1259–1263[Abstract/Free Full Text]
  92. Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M 1997 Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3:231–234[CrossRef][Medline]
  93. Ikeda H, Yoshimoto T, Shida N 1997 Molecular analysis of p21 and p27 genes in human pituitary adenomas. Br J Cancer 76:1119–1123[Medline]
  94. Tanaka C, Yoshimoto K, Yang P, Kimura T, Yamada S, Moritani M, Sano T, Itakura M 1997 Infrequent mutations of p27Kip1 gene and trisomy 12 in a subset of human pituitary adenomas. J Clin Endocrinol Metab 82:3141–3147[Abstract/Free Full Text]
  95. Jin L, Qian X, Kulig E, Sanno N, Scheithauer BW, Kovacs K, Young Jr WF, Lloyd RV 1997 Transforming growth factor-ß, transforming growth factor-ß receptor II, and p27Kip1 expression in nontumorous and neoplastic human pituitaries. Am J Pathol 151:509–519[Abstract]
  96. Lloyd RV, Jin L, Qian X, Kulig E 1997 Aberrant p27 kip1 expression in endocrine and other tumors. Am J Pathol 150:401–407[Abstract]
  97. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M 1995 Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269:682–685[Abstract/Free Full Text]
  98. Vlach J, Hennecke S, Amati B 1997 Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J 16:5334–5344[CrossRef][Medline]
  99. Tam SW, Theodoras AM, Pagano M 1997 Kip1 degradation via the ubiquitin-proteasome pathway. Leukemia 11:363–366
  100. Dybdal NO, Hargreaves KM, Madigan JE, Gribble DH, Kennedy PC, Stabenfeldt GH 1994 Diagnostic testing for pituitary pars intermedia dysfunction in horses. J Am Vet Med Assoc 204:627–632[Medline]
  101. Eiler H, Oliver JW, Andrews FM, Fecteau KA, Green EM, McCracken M 1997 Results of a combined dexamethasone suppression/thyrotropin-releasing hormone stimulation test in healthy horses and horses suspected to have a pars intermedia pituitary adenoma. J Am Vet Med Assoc 211:79–81[Medline]
  102. Peterson ME, Orth DN, Halmi NS, Zielinski AC, Davis DR, Chavez FT, Drucker WD 1986 Plasma immunoreactive proopiomelanocortin peptides and cortisol in normal dogs and dogs with Addison’s disease and Cushing’s syndrome: basal concentrations. Endocrinology 119:720–730[Abstract/Free Full Text]
  103. Franklin DS, Godfrey VL, Lee H, Kovalev GI, Schoonhoven R, Chen-Kiang S, Su L, Xiong Y 1998 CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 12:2899–2911[Abstract/Free Full Text]
  104. Burgess JR, Shepherd JJ, Parameswaran V, Hoffman L, Greenaway TM 1996 Prolactinomas in a large kindred with multiple endocrine neoplasia type 1: clinical features and inheritance pattern. J Clin Endocrinol Metab 81:1841–1845[Abstract]
  105. Burgess JR, Shepherd JJ, Parameswaran V, Hoffman L, Greenaway TM 1996 Spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN 1): clinical, biochemical, and radiological features of pituitary disease in a large MEN 1 kindred. J Clin Endocrinol Metab 81:2642–2646[Abstract]
  106. Nakamura Y, Larsson C, Julier C, Bystrom C, Skogseid B, Wells S, Oberg K, Carlson M, Taggart T, O’Connell P, Leppert M, Lalouel J-M, Nordenskjold M, White R 1989 Localization of the genetic defect in multiple endocrine neoplasia type 1 within a small region of chromosome 11. Am J Hum Genet 44:751–755[Medline]
  107. Larsson C, Skosgeid B, Öberg K, Nakamura Y, Nordenskjöld M 1988 Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332:85–87[CrossRef][Medline]
  108. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ 1997 Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404–407[Abstract/Free Full Text]
  109. Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J, Lenoir G, Pugeat M, Calender A, Parente F, Quincey D, Gaudray P, De Wit MJ, Lips CJ, Hoppener JW, Khodaei S, Grant AL, Weber G, Kytola S, Teh BT, Farnebo F, Phelan C, Hayward W, Larsson C, Pannett AAJ, Forbes SA, Duncan Bassett JH, Thakker RV 1997 Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet 6:1177–1183[Abstract/Free Full Text]
  110. Guru SC, Agarwal SK, Manickam P, Olufemi SE, Crabtree JS, Weisemann JM, Kester MB, Kim YS, Wang Y, Emmert-Buck MR, Liotta LA, Spiegel AM, Boguski MS, Roe BA, Collins FS, Marx SJ, Burns L, Chandrasekharappa SC 1997 A transcript map for the 2.8-Mb region containing the multiple endocrine neoplasia type 1 locus [letter]. Genome Res 7:725–735[Abstract/Free Full Text]
  111. Emmert-Buck MR, Lubensky IA, Dong Q, Manickam P, Guru SC, Kester MB, Olufemi SE, Agarwal S, Burns AL, Spiegel AM, Collins FS, Marx SJ, Zhuang Z, Liotta LA, Chandrasekharappa SC, Debelenko LV 1997 Localization of the multiple endocrine neoplasia type I (MEN1) gene based on tumor loss of heterozygosity analysis. Cancer Res 57:1855–1858[Abstract/Free Full Text]
  112. Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC, Doppman JL, Kim YS, Lubensky IA, Zhuang Z, Green JS, Guru SC, Manickam P, Olufemi SE, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ 1997 Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 6:1169–1175[Abstract/Free Full Text]
  113. Tanaka C, Yoshimoto K, Yamada S, Nishioka H, Ii S, Moritani M, Yamaoka T, Itakura M 1998 Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese. J Clin Endocrinol Metab 83:960–965[Abstract/Free Full Text]
  114. Teh BT, Kytola S, Farnebo F, Bergman L, Wong FK, Weber G, Hayward N, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjaerg L, Jorde R, Menon J, Khir A, Tan TT, Chan SP, Zaini A, Khalid BAK, Sandelin K, Thompson N, Brandi M-L, Warth M, Stock J, Leisti J, Cameron D, Shepherd JJ, Oberg K, Nordenskjold M, Salmela P 1998 Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 83:2621–2626[Abstract/Free Full Text]
  115. Clayton RN, Boggild M, Bates AS, Bicknell J, Simpson D, Farrell W 1997 Tumour suppressor genes in the pathogenesis of human pituitary tumours. Horm Res 47:185–193[Medline]
  116. Bystrom C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B, Oberg K, Werner S, Nordenskjold M 1990 Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Proc Natl Acad Sci USA 87:1968–1972[Abstract/Free Full Text]
  117. Thakker RV 1993 The molecular genetics of the multiple endocrine neoplasia syndromes. Clin Endocrinol (Oxf) 38:1–14[Medline]
  118. Zhuang Z, Ezzat SZ, Vortmeyer AO, Weil R, Oldfield EH, Park WS, Pack S, Huang S, Agarwal SK, Guru SC, Manickam P, Debelenko LV, Kester MB, Olufemi SE, Heppner C, Crabtree JS, Burns AL, Spiegel AM, Marx SJ, Chandrasekharappa SC, Collins FS, Emmert-Buck MR, Liotta LA, Asa SL, Lubensky IA 1997 Mutations of the MEN1 tumor suppressor gene in pituitary tumors. Cancer Res 57:5446–5451[Abstract/Free Full Text]
  119. Prezant TR, Levine J, Melmed S 1998 Molecular characterization of the men1 tumor suppressor gene in sporadic pituitary tumors. J Clin Endocrinol Metab 83:1388–1391[Abstract/Free Full Text]
  120. Asa SL, Somers K, Ezzat S 1998 The MEN-1 gene is rarely down-regulated in pituitary adenomas. J Clin Endocrinol Metab 83:3210–3212[Abstract/Free Full Text]
  121. Satta M, Korbonits M, Jacobs RA, Bolden-Dwinfour DA, Kaltsas GA, Vangeli V, Adams E, Fahlbusch R, Grossman AB 1999 Expression of menin gene mRNA in pituitary tumours. Eur J Endocrinol, in press
  122. Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert JP, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Meyrier A, Caron P, Vantyghem M-C, Assayag M, Peix J-L, Pugeat M, Rohmer V, Vallotton M, Lenoir G, Gaudray P, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar D, Murat A, Calender A 1998 Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet 63:455–467[CrossRef][Medline]
  123. Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS, Chandrasekharappa SC 1998 Menin, the product of the MEN1 gene, is a nuclear protein. Proc Natl Acad Sci USA 95:1630–1634[Abstract/Free Full Text]
  124. Varrault A, Ciani E, Apiou F, Bilanges B, Hoffmann A, Pantaloni C, Bockaert J, Spengler D, Journot L 1998 hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer. Proc Natl Acad Sci USA 95:8835–8840[Abstract/Free Full Text]
  125. Abdollahi A, Roberts D, Godwin AK, Schultz DC, Sonoda G, Testa JR, Hamilton TC 1997 Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors. Oncogene 14:1973–1979[CrossRef][Medline]
  126. Spengler D, Villalba M, Hoffmann A, Pantaloni C, Houssami S, Bockaert J, Journot L 1997 Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain. EMBO J 16:2814–2825[CrossRef][Medline]
  127. Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, Sobel ME 1988 Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80:200–204[Abstract/Free Full Text]
  128. Steeg PS, Cohn KH, Leone A 1991 Tumor metastasis and nm23: current concepts. Cancer Cells 3:257–262[Medline]
  129. Steeg PS, de la Rosa A, Flatow U, MacDonald NJ, Benedict M, Leone A 1993 Nm23 and breast cancer metastasis. Breast Cancer Res Treat 25:175–187[CrossRef][Medline]
  130. Golden A, Benedict M, Shearn A, Kimura N, Leone A, Liotta LA, Steeg PS 1992 Nucleoside diphosphate kinases, nm23, and tumor metastasis: possible biochemical mechanisms. Cancer Treat Res 63:345–358[Medline]
  131. Freije JM, MacDonald NJ, Steeg PS 1996 Differential gene expression in tumor metastasis: Nm23. Curr Top Microbiol Immunol 213:215–232
  132. Takino H, Herman V, Weiss M, Melmed S 1995 Purine-binding factor (nm23) gene expression in pituitary tumors: marker of adenoma invasiveness. J Clin Endocrinol Metab 80:1733–1738[Abstract/Free Full Text]
  133. Bates AS, Buckley N, Boggild MD, Bicknell EJ, Perrett CW, Broome JC, Clayton RN 1995 Clinical and genetic changes in a case of a Cushing’s carcinoma. Clin Endocrinol (Oxf) 42:663–670[Medline]
  134. Levine S 1994 The ontogeny of the hypothalamic-pituitary-adrenal axis. The influence of maternal factors. Ann N Y Acad Sci 746:275–288[Medline]
  135. Makara GB, Kiss A, Lolait SJ, Aguilera G 1996 Hypothalamic-pituitary corticotroph function after shunting of magnocellular vasopressin and oxytocin to the hypophyseal portal circulation. Endocrinology 137:580–586[Abstract]
  136. Dorin RI, Ferries LM, Roberts B, Qualls CR, Veldhuis JD, Lisansky EJ 1996 Assessment of stimulated and spontaneous adrenocorticotropin secretory dynamics identifies distinct components of cortisol feedback inhibition in healthy humans. J Clin Endocrinol Metab 81:3883–3891[Abstract/Free Full Text]
  137. Antoni FA 1993 Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Front Neuroendocrinol 14:76–122[CrossRef][Medline]
  138. Matthews SG, Challis JR 1997 CRH and AVP-induced changes in synthesis and release of ACTH from the ovine fetal pituitary in vitro: negative influences of cortisol. Endocrine 6:293–300[Medline]
  139. LeBeau AP, Robson AB, McKinnon AE, Donald RA, Sneyd J 1997 Generation of action potentials in a mathematical model of corticotrophs. Biophys J 73:1263–1275[Medline]
  140. Rosenfeld P, Suchecki D, Levine S 1992 Multifactorial regulation of the hypothalamic-pituitary-adrenal axis during development. Neurosci Biobehav Rev 16:553–568[CrossRef][Medline]
  141. Grino M, Paulmyer-Lacroix O, Anglade G, Oliver C 1995 Molecular aspects of the regulation of the hypothalamo-pituitary-adrenal axis during development in the rat. Ann NY Acad Sci 771:339–351[CrossRef][Medline]
  142. Baertschi AJ, Friedli M 1985 A novel type of vasopressin receptor on anterior pituitary corticotrophs? Endocrinology 116:499–502[Abstract/Free Full Text]
  143. Buckingham JC 1985 Two distinct corticotrophin releasing activities of vasopressin. Br J Pharmacol 84:213–219[Medline]
  144. Aguilera G 1994 Regulation of pituitary ACTH secretion during chronic stress. Front Neuroendocrinol 15:321–350[CrossRef][Medline]
  145. Liu JP, Robinson PJ, Funder JW, Engler D 1990 The biosynthesis and secretion of adrenocorticotropin by the ovine anterior pituitary is predominantly regulated by arginine vasopressin (AVP). Evidence that protein kinase C mediates the action of AVP. J Biol Chem 265:14136–14142[Abstract/Free Full Text]
  146. Castro MG, Gusovsky F, Loh YP 1989 Transmembrane signals mediating adrenocorticotropin release from mouse anterior pituitary cells. Mol Cell Endocrinol 65:165–173[CrossRef][Medline]
  147. Thibonnier M, Auzan C, Madhun Z, Wilkins P, Berti-Mattera L, Clauser E 1994 Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor. J Biol Chem 269:3304–3310[Abstract/Free Full Text]
  148. Fox AW 1988 Vascular vasopressin receptors. Gen Pharmacol 19:639–647[Medline]
  149. Sugimoto T, Saito M, Mochizuki S, Watanabe Y, Hashimoto S, Kawashima H 1994 Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor. J Biol Chem 269:27088–27092[Abstract/Free Full Text]
  150. de Keyzer Y, Auzan C, Lenne F, Beldjord C, Thibonnier M, Bertagna X, Clauser E 1994 Cloning and characterization of the human V3 pituitary vasopressin receptor. FEBS Lett 356:215–220[CrossRef][Medline]
  151. Pan Y, Metzenberg A, Das S, Jing B, Gitschier J 1992 Mutations in the V2 vasopressin receptor gene are associated with X-linked nephrogenic diabetes insipidus. Nat Genet 2:103–106[CrossRef][Medline]
  152. Rosenthal W, Antaramian A, Gilbert S, Birnbaumer M 1993 Nephrogenic diabetes insipidus. A V2 vasopressin receptor unable to stimulate adenylyl cyclase. J Biol Chem 268:13030–13033[Abstract/Free Full Text]
  153. Seibold A, Rosenthal W, Barberis C, Birnbaumer M 1993 Cloning of the human type-2 vasopressin receptor gene. Ann NY Acad Sci 689:570–572[CrossRef][Medline]
  154. Barberis C, Seibold A, Ishido M, Rosenthal W, Birnbaumer M 1993 Expression cloning of the human V2 vasopressin receptor. Regul Pept 45:61–66[CrossRef][Medline]
  155. Antoni FA 1987 Receptors mediating the CRH effects of vasopressin and oxytocin. Ann NY Acad Sci 512:195–204[Medline]
  156. Richter D 1988 Molecular events in expression of vasopressin and oxytocin and their cognate receptors. Am J Physiol 255:F207–219
  157. Jard S 1988 Mechanisms of action of vasopressin and vasopressin antagonists. Kidney Int Suppl 26:S38–S42
  158. Carmichael MC, Kumar R 1994 Molecular biology of vasopressin receptors. Semin Nephrol 14:341–348[Medline]
  159. Spiegel AM 1996 Defects in G protein-coupled signal transduction in human disease. Annu Rev Physiol 58:143–170[CrossRef][Medline]
  160. Dahia PL, Ahmed-Shuaib A, Jacobs RA, Chew SL, Honegger J, Fahlbusch R, Besser GM, Grossman AB 1996 Vasopressin receptor expression and mutation analysis in corticotropin-secreting tumors. J Clin Endocrinol Metab 81:1768–1771[Abstract]
  161. Malerbi DA, Mendonca BB, Liberman B, Toledo SP, Corradini MC, Cunha-Neto MB, Fragoso MC, Wajchenberg BL 1993 The desmopressin stimulation test in the differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 38:463–472[Medline]
  162. Newell-Price J, Perry L, Medbak S, Monson J, Savage M, Besser M, Grossman A 1997 A combined test using desmopressin and corticotropin-releasing hormone in the differential diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 82:176–181[Abstract/Free Full Text]
  163. Colombo P, Passini E, Re T, Faglia G, Ambrosi B 1997 Effect of desmopressin on ACTH and cortisol secretion in states of ACTH excess. Clin Endocrinol (Oxf) 46:661–668[CrossRef][Medline]
  164. Rabadan-Diehl C, Makara G, Kiss A, Lolait S, Zelena D, Oche-dalski T, Aguilera G 1997 Regulation of pituitary V1b vasopressin receptor messenger ribonucleic acid by adrenalectomy and glucocorticoid administration. Endocrinology 138:5189–5194[Abstract/Free Full Text]
  165. Thibonnier M, Preston JA, Dulin N, Wilkins PL, Berti-Mattera LN, Mattera R 1997 The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways. Endocrinology 138:4109–4122[Abstract/Free Full Text]
  166. Arlt W, Dahia PLM, Callies F, Nordmeyer JP, Allolio B, Grossman AB, Reincke M 1997 Ectopic ACTH production by a bronchial carcinoid tumour responsive to desmopressin in vivo and in vitro. Clin Endocrinol (Oxf) 47:623–627[CrossRef][Medline]
  167. Scott LV, Dinan TG 1998 Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis function: implications for the pathophysiology of depression. Life Sci 62:1985–1998[CrossRef][Medline]
  168. de Goeij DC, Kvetnansky R, Whitnall MH, Jezova D, Berkenbosch F, Tilders FJ 1991 Repeated stress-induced activation of corticotropin-releasing factor neurons enhances vasopressin stores and colocalization with corticotropin-releasing factor in the median eminence of rats. Neuroendocrinology 53:150–159[Medline]
  169. de Goeij DC, Jezova D, Tilders FJ 1992 Repeated stress enhances vasopressin synthesis in corticotropin releasing factor neurons in the paraventricular nucleus. Brain Res 577:165–168[CrossRef][Medline]
  170. Rabadan-Diehl C, Lolait SJ, Aguilera G 1995 Regulation of pituitary vasopressin V1b receptor mRNA during stress in the rat. J Neuroendocrinol 7:903–910[CrossRef][Medline]
  171. Sonino N, Fava GA, Boscaro M 1993 A role for life events in the pathogenesis of Cushing’s disease. Clin Endocrinol (Oxf) 38:261–264[Medline]
  172. Karl M, Lamberts SW, Koper JW, Katz DA, Huizenga NE, Kino T, Haddad BR, Hughes MR, Chrousos GP 1996 Cushing’s disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. Proc Assoc Am Physicians 108:296–307[Medline]
  173. Trainer PJ, Grossman A 1991 The diagnosis and differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 34:317–330[Medline]
  174. Orth DN 1995 Cushing’s syndrome. N Engl J Med 332:791–803[Free Full Text]
  175. Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM 1985 Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318:635–641[CrossRef][Medline]
  176. Hollenberg SM, Giguere V, Segui P, Evans RM 1987 Colocalization of DNA-binding and transcriptional activation functions in the human glucocorticoid receptor. Cell 49:39–46[CrossRef][Medline]
  177. Gustafsson JA, Carlstedt-Duke J, Stromstedt PE, Wikstrom AC, Denis M, Okret S, Dong Y 1990 Structure, function and regulation of the glucocorticoid receptor. Prog Clin Biol Res 322:65–80[Medline]
  178. Gehring U 1986 Genetics of glucocorticoid receptors. Mol Cell Endocrinol 48:89–96[CrossRef][Medline]
  179. Carlstedt-Duke J, Stromstedt PE, Wrange O, Bergman T, Gustafsson JA, Jornvall H 1987 Domain structure of the glucocorticoid receptor protein. Proc Natl Acad Sci USA 84:4437–4440[Abstract/Free Full Text]
  180. Wright AP, Zilliacus J, McEwan IJ, Dahlman-Wright K, Almlof T, Carlstedt-Duke J, Gustafsson JA 1993 Structure and function of the glucocorticoid receptor. J Steroid Biochem Mol Biol 47:11–19[CrossRef][Medline]
  181. Oakley RH, Webster JC, Sar M, Parker Jr CR, Cidlowski JA 1997 Expression and subcellular distribution of the ß-isoform of the human glucocorticoid receptor. Endocrinology 138:5028–5038[Abstract/Free Full Text]
  182. Leung DYM, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, Chrousos GP, Klemm DJ 1997 Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor ß. J Exp Med 186:1567–1574[Abstract/Free Full Text]
  183. Bamberger CM, Schulte HM, Chrousos GP 1996 Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 17:245–261[Abstract/Free Full Text]
  184. de Castro M, Elliot S, Kino T, Bamberger C, Karl M, Webster E, Chrousos GP 1996 The non-ligand binding ß-isoform of the human glucocorticoid receptor (hGR ß): tissue levels, mechanism of action, and potential physiologic role. Mol Med 2:597–607[Medline]
  185. Lamberts SW 1996 The glucocorticoid insensitivity syndrome. Horm Res 45[Suppl 1]:2–4
  186. Stratakis CA, Karl M, Schulte HM, Chrousos GP 1994 Glucocorticosteroid resistance in humans. Elucidation of the molecular mechanisms and implications for pathophysiology. Ann NY Acad Sci 746:362–374[Medline]
  187. Chrousos GP, Castro M, Leung DY, Webster E, Kino T, Bamberger C, Elliot S, Stratakis C, Karl M 1996 Molecular mechanisms of glucocorticoid resistance/hypersensitivity. Potential clinical implications. Am J Respir Crit Care Med 154: S39–S43
  188. de Castro M, Chrousos GP 1997 Glucocorticoid resistance. Curr Ther Endocrinol Metab 6:188–189[Medline]
  189. de Lange P, Koper JW, Huizenga NA, Brinkmann AO, de Jong FH, Karl M, Chrousos GP, Lamberts SW 1997 Differential hormone-dependent transcriptional activation and -repression by naturally occurring human glucocorticoid receptor variants. Mol Endocrinol 11:1156–1164[Abstract/Free Full Text]
  190. Karl M, Von Wichert G, Kempter E, Katz DA, Reincke M, Monig H, Ali IU, Stratakis CA, Oldfield EH, Chrousos GP, Schulte HM 1996 Nelson’s syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene. J Clin Endocrinol Metab 81:124–129[Abstract]
  191. Kemink SAG, Smals AGH, Hermus A, Pieters G, Kloppenborg PWC 1997 Nelson’s syndrome — a review. Endocrinologist 7:5–9
  192. Dahia PL, Honegger J, Reincke M, Jacobs RA, Mirtella A, Fahlbusch R, Besser GM, Chew SL, Grossman AB 1997 Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors. J Clin Endocrinol Metab 82:1088–1093[Abstract/Free Full Text]
  193. Huizenga NA, de Lange P, Koper JW, Clayton RN, Farrell WE, van der Lely AJ, Brinkmann AO, de Jong FH, Lamberts SW 1998 Human adrenocorticotropin-secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locus. J Clin Endocrinol Metab 83:917–921[Abstract/Free Full Text]
  194. Arai K, Chrousos GP 1994 Hormone-nuclear receptor interactions in health and disease. Glucocorticoid resistance. Baillieres Clin Endocrinol Metab 8:317–331[CrossRef][Medline]
  195. Liaw CW, Lovenberg TW, Barry G, Oltersdorf T, Grigoriadis DE, de Souza EB 1996 Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid. Endocrinology 137:72–77[Abstract]
  196. Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, De Souza EB, Oltersdorf T 1995 Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc Natl Acad Sci USA 92:836–840[Abstract/Free Full Text]
  197. de Bustros A, Nelkin BD, Silverman A, Ehrlich G, Poiesz B, Baylin SB 1988 The short arm of chromosome 11 is a "hot spot" for hypermethylation in human neoplasia. Proc Natl Acad Sci USA 85:5693–5697[Abstract/Free Full Text]
  198. De Souza EB 1995 Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology 20:789–819[CrossRef][Medline]
  199. Dieterich KD, Lehnert H, De Souza EB 1997 Corticotropin-releasing factor receptors: an overview. Exp Clin Endocrinol Diabetes 105:65–82[Medline]
  200. Chen R, Lewis KA, Perrin MH, Vale WW 1993 Expression cloning of a human corticotropin-releasing-factor receptor. Proc Natl Acad Sci USA 90:8967–8971[Abstract/Free Full Text]
  201. Chang CP, Pearse II RV, O’Connell S, Rosenfeld MG 1993 Identification of a seven transmembrane helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain. Neuron 11:1187–1195[CrossRef][Medline]
  202. Xiong Y, Xie LY, Abou-Samra AB 1995 Signaling properties of mouse and human corticotropin-releasing factor (CRF) receptors: decreased coupling efficiency of human type II CRF receptor. Endocrinology 136:1828–1834[Abstract]
  203. Ross PC, Kostas CM, Ramabhadran TV 1994 A variant of the human corticotropin-releasing factor (CRF) receptor: cloning, expression and pharmacology. Biochem Biophys Res Commun 205:1836–1842[CrossRef][Medline]
  204. Potter E, Sutton S, Donaldson C, Chen R, Perrin M, Lewis K, Sawchenko PE, Vale W 1994 Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary. Proc Natl Acad Sci USA 91:8777–8781[Abstract/Free Full Text]
  205. Luo X, Kiss A, Rabadan-Diehl C, Aguilera G 1995 Regulation of hypothalamic and pituitary corticotropin-releasing hormone receptor messenger ribonucleic acid by adrenalectomy and glucocorticoids. Endocrinology 136:3877–3883[Abstract]
  206. de Keyzer Y, Rene P, Beldjord C, Lenne F, Bertagna X 1998 Overexpression of vasopressin (V3) and corticotropin-releasing hormone receptors in corticotroph tumors. Clin Endocrinol (Oxf) 49:475–82[CrossRef][Medline]
  207. Dieterich KD, Gundelfinger ED, Ludecke DK, Lehnert H 1998 Mutation and expression analysis of corticotropin-releasing factor 1 receptor in adrenocorticotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 83:3327–3331[Abstract/Free Full Text]
  208. Abs R, Smets G, Vauquelin G, Verhelst J, Mahler C, Verlooy J, Stevenaert A, Wouters L, Borgers M, Beckers A 1997 125I-Tyr0-hCRH labelling characteristics of corticotropin-releasing hormone receptors: differences between normal and adenomatous corticotrophs. Neurochem Int 30:291–297[CrossRef][Medline]
  209. Sakai Y, Horiba N, Sakai K, Tozawa F, Kuwayama A, Demura H, Suda T 1997 Corticotropin-releasing factor up-regulates its own receptor gene expression in corticotropic adenoma cells in vitro. J Clin Endocrinol Metab 82:1229–1234[Abstract/Free Full Text]
  210. Sakai K, Horiba N, Sakai Y, Tozawa F, Demura H, Suda T 1996 Regulation of corticotropin-releasing factor receptor messenger ribonucleic acid in rat anterior pituitary. Endocrinology 137:1758–1763[Abstract]
  211. Hazel TG, Nathans D, Lau LF 1988 A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci USA 85:8444–8448[Abstract/Free Full Text]
  212. Milbrandt J 1988 Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1:183–188[CrossRef][Medline]
  213. Ryseck RP, Macdonald-Bravo H, Mattei MG, Ruppert S, Bravo R 1989 Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J 8:3327–3335[Medline]
  214. Wilson TE, Mouw AR, Weaver CA, Milbrandt J, Parker KL 1993 The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. Mol Cell Biol 13:861–868[Abstract/Free Full Text]
  215. Philips A, Maira M, Mullick A, Chamberland M, Lesage S, Hugo P, Drouin J 1997 Antagonism between Nur77 and glucocorticoid receptor for control of transcription. Mol Cell Biol 17:5952–5959[Abstract]
  216. Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J 1997 Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 17:5946–5951[Abstract]
  217. Drouin J, Maira M, Philips A 1998 Novel mechanism of action for Nur77 and antagonism by glucocorticoids: a convergent mechanism for CRH activation and glucocorticoid repression of POMC gene transcription. J Steroid Biochem Mol Biol 65:59–63[CrossRef][Medline]
  218. Davis IJ, Lau LF 1994 Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands. Mol Cel Biol 14:3469–3483[Abstract/Free Full Text]
  219. Okabe T, Takayanagi R, Adachi M, Imasaki K, Nawata H 1998 Nur77, a member of the steroid receptor subfamily, antagonizes negative feedback of ACTH synthesis and secretion by glucocorticoid in pituitary corticotrope cells. J Endocrinol 156:169–175[Abstract]
  220. Crawford PA, Sadovsky Y, Woodson K, Lee SL, Milbrandt J 1995 Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice. Mol Cell Biol 15:4331–4316[Abstract]
  221. Korbonits M, Grossman AB 1995 Growth hormone-releasing peptide and its analogues; novel stimuli to growth hormone release. Trends Endocrinol Metab 6:43–49
  222. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJS, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH 1996 A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974–977
  223. Renner U, Brockmeier S, Strasburger CJ, Lange M, Schopohl J, Muller OA, von Werder K, Stalla GK 1994 Growth hormone (GH)-releasing peptide stimulation of GH release from human somatotroph adenoma cells: interaction with GH-releasing hormone, thyrotropin-releasing hormone, and octreotide. J Clin Endocrinol Metab 78:1090–1096[Abstract]
  224. Ghigo E, Arvat E, Ramunni J, Colao A, Gianotti L, Deghenghi R, Lombardi G, Camanni F 1997 Adrenocorticotropin- and cortisol-releasing effect of hexarelin, a synthetic growth hormone-releasing peptide, in normal subjects and patients with Cushing’s syndrome. J Clin Endocrinol Metab 82:2439–2444[Abstract/Free Full Text]
  225. Korbonits M, Jacobs RJ, Aylwin SJB, Burrin JM, Dahia PLM, Monson J, Trainer PJ, Chew SL, Besser GM, Grossman AB 1998 Expression of the growth hormone secretagogue receptor in pituitary adenomas and other neuroendocrine tumors. J Clin Endocrinol Metab 83:3624–3630[Abstract/Free Full Text]
  226. Patterson PH 1992 The emerging neuropoietic cytokine family: first CDF/LIF, CNTF, and IL-6; next ONC, MGF, GCSF? Curr Biol 2:94–97
  227. Kishimoto T, Taga T, Akira S 1994 Cytokine signal transduction. Cell 76:253–262[CrossRef][Medline]
  228. Stefana B, Ray DW, Melmed S 1996 Leukemia inhibitory factor induces differentiation of pituitary corticotroph function: an immuno-neuroendocrine phenotypic switch. Proc Natl Acad Sci USA 93:12502–12506[Abstract/Free Full Text]
  229. Pepper M, Ferrara N, Orci L, Montesano R 1995 Leukemia inhibitory factor (LIF) inhibits angiogenesis in vitro. J Cell Sci 108:73–83[Abstract]
  230. Ferrara N, Winer J, Henzel WJ 1992 Pituitary follicular cells secrete an inhibitor of aortic endothelial cell growth: identification as leukemia inhibitory factor. Proc Natl Acad Sci USA 89:698–702[Abstract/Free Full Text]
  231. Akita S, Malkin J, Melmed S 1996 Disrupted murine leukemia inhibitory factor (LIF) gene attenuates adrenocorticotropic hormone (ACTH) secretion. Endocrinology 137:3140–3143[Abstract]
  232. Akita S, Readhead C, Stefaneanu L, Fine J, Tampanaru-Sarmesiu A, Kovacs K, Melmed S 1997 Pituitary-directed leukemia inhibitory factor transgene forms Rathke’s cleft cysts and impairs adult pituitary function. A model for human pituitary Rathke’s cysts. J Clin Invest 99:2462–2469[Medline]
  233. Yano H, Readhead C, Nakashima M, Ren SG, Melmed S 1998 Pituitary-directed leukemia inhibitory factor transgene causes Cushing’s syndrome: neuro-immune-endocrine modulation of pituitary development. Mol Endocrinol 12:1708–1720[Abstract/Free Full Text]
  234. Childs GV, Rougeau D, Unabia G 1995 Corticotropin-releasing hormone and epidermal growth factor: mitogens for anterior pituitary corticotropes. Endocrinology 136:1595–1602[Abstract]
  235. Luger A, Calogero AE, Kalogeras K, Galucci WT, Gold PW, Loriaux DL, Chrousos GP 1988 Interaction of epidermal growth factor with the hypothalamic-pituitary-adrenal axis: potential physiologic relevance. J Clin Endocrinol Metab 66:334–346[Abstract/Free Full Text]
  236. Kontogeorgos G, Stefaneanu L, Kovacs K, Cheng Z 1996 Localization of epidermal growth factor (EGF) and epidermal growth receptor (EGFr) in human pituitaries: an immunohistochemical study. Endocr Pathol 7:63–70[Medline]
  237. LeRiche VK, Asa SL, Ezzat S 1996 Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 81:656–662[Abstract]
  238. Chaidarun SS, Eggo MC, Sheppard MC, Stewart PM 1994 Expression of epidermal growth factor (EGF), its receptor, and related oncoprotein (ERBb-2) in human pituitary tumors and response to EGF in vitro. Endocrinology 135:2012–2021[Abstract]
  239. Ray D, Melmed S 1997 Pituitary cytokine and growth factor expression and action. Endocr Rev 18:206–228[Abstract/Free Full Text]
  240. McAndrew J, Paterson AJ, Asa SL, McCarthy KJ, Kudlow JE 1995 Targeting of transforming growth factor-{alpha} expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas. Endocrinology 136:4479–4488[Abstract]
  241. Borreli E, Sawchenko PE, Evans RM 1992 Pituitary hyperplasia induced by ectopic expression of nerve growth factor. Proc Natl Acad Sci USA 89:2764–2768[Abstract/Free Full Text]
  242. Sawada T, Koike K, Kanda Y, Ikegami H, Jikihara H, Maeda T, Osako Y, Hirota K, Miyake A 1995 Interleukin-6 stimulates cell proliferation of rat pituitary clonal cell lines in vitro. J Endocrinol Invest 18:83–90[Medline]
  243. Shimon I, Huttner A, Said J, Spirina OM, Melmed S 1996 Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription. J Clin Invest 97:187–195[Medline]
  244. Vrontakis ME, Sano T, Kovacs K, Friesen HG 1990 Presence of galanin-like immunoreactivity in nontumorous corticotrophs and corticotroph adenomas of the human pituitary. J Clin Endocrinol Metab 70:747–751[Abstract/Free Full Text]
  245. Wynick D, Hammond PJ, Akinsanya KO, Bloom SR 1993 Galanin regulates basal and oestrogen-stimulated lactotroph function. Nature 364:529–532[CrossRef][Medline]
  246. Alexandrow MG, Moses HL 1995 Transforming growth factor ß and cell cycle regulation. Cancer Res 55:1452–1457[Free Full Text]
  247. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, Brattain M, Willson JKV 1995 Inactivation of the type II TGF-ß receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338[Abstract/Free Full Text]
  248. Bach I, Carriere C, Ostendorff HP, Andersen B, Rosenfeld MG 1997 A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins. Genes Dev 11:1370–1380[Abstract/Free Full Text]
  249. Baker BL, Jaffe RB 1975 The genesis of cell types in the adenohypophysis of the human fetus as observed with immunocytochemistry. Am J Anat 143:137–161[CrossRef][Medline]
  250. Asa SL, Kovacs K 1984 Functional morphology of the human fetal pituitary. Pathol Annu 19:275–315
  251. Lugo DI, Pintar JE 1996 Ontogeny of basal and regulated secretion from POMC cells of the developing anterior lobe of the rat pituitary gland. Dev Biol 173:95–109[CrossRef][Medline]
  252. Girardin SE, Benjannet S, Barale JC, Chretien M, Seidah NG 1998 The LIM homeobox protein mLIM3/Lhx3 induces expression of the prolactin gene by a Pit-1/GHF-1-independent pathway in corticotroph AtT20 cells. FEBS Lett 431:333–338[CrossRef][Medline]
  253. Shang J, Luo Y, Clayton DA 1997 Backfoot is a novel homeobox gene expressed in the mesenchyme of developing hind limb. Dev Dyn 209:242–253[CrossRef][Medline]
  254. Lanctot C, Lamolet B, Drouin J 1997 The bicoid-related homeoprotein Ptx1 defines the most anterior domain of the embryo and differentiates posterior from anterior lateral mesoderm. Development 124:2807–2817[Abstract]
  255. 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]
  256. Tremblay JJ, Lanctot C, Drouin J 1998 The pan-pituitary activator of transcripiton, 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
  257. Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW, Datson NA, Siegel-Bartelt J, Bierke-Nelson D, Bitoun P, Zabel BU, Carey JC, Murray JC 1996 Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392–399[CrossRef][Medline]
  258. Gage PJ, Camper SA 1997 Pituitary homeobox 2, a novel member of the bicoid-related family of homeobox genes, is a potential regulator of anterior structure formation. Hum Mol Genet 6:457–464[Abstract/Free Full Text]
  259. Sadeghi-Nejad A, Senior B 1974 Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger’s syndrome). J Pediatr 85:644–648[CrossRef][Medline]
  260. Semina EV, Reiter RS, Murray JC 1997 Isolation of a new homeobox gene belonging to the Pitx/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum Mol Genet 6:2109–2116[Abstract/Free Full Text]
  261. Cillo C 1994 HOX genes in human cancers. Invasion Metastasis 14:38–49[Medline]
  262. De Vita G, Barba P, Odartchenko N, Givel JC, Freschi G, Bucciarelli G, Magli MC, Boncinelli E, Cillo C 1993 Expression of homeobox-containing genes in primary and metastatic colorectal cancer. Eur J Cancer 29A:887–893
  263. 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]
  264. Ryan AK, Rosenfeld MG 1997 POU domain family values: flexibility, partnerships, and developmental codes. Genes Dev 11:1207–1225[Free Full Text]
  265. 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]
  266. Gruber CA, Rhee JM, Gleiberman A, Turner EE 1997 POU domain factors of the Brn-3 class recognize functional DNA elements which are distinctive, symmetrical, and highly conserved in evolution. Mol Cell Biol 17:2391–2400[Abstract]
  267. Gerrero MR, McEvilly RJ, Turner E, Lin CR, O’Connell S, Jenne KJ, Hobbs MV, Rosenfeld MG 1993 Brn-3.0: a POU-domain protein expressed in the sensory, immune, and endocrine systems that functions on elements distinct from known octamer motifs. Proc Natl Acad Sci USA 90:10841–10845[Abstract/Free Full Text]
  268. Theil T, McLean-Hunter S, Zornig M, Moroy T 1993 Mouse Brn-3 family of POU transcription factors: a new aminoterminal domain is crucial for the oncogenic activity of Brn-3a. Nucleic Acids Res 21:5921–5929[Abstract/Free Full Text]
  269. Rosenfeld MG, Bach I, Erkman L, Li P, Lin C, Lin S, McEvilly R, Ryan A, Rhodes S, Schonnemann M, Scully K 1996 Transcriptional control of cell phenotypes in the neuroendocrine system. Recent Prog Horm Res 51:217–238
  270. Smith MD, Dawson SJ, Latchman DS 1997 The Brn-3a transcription factor induces neuronal process outgrowth and the coordinate expression of genes encoding synaptic proteins. Mol Cell Biol 17:345–354[Abstract]
  271. 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]
  272. Leblond-Francillard M, Picon A, Bertagna X, de Keyzer Y 1997 High expression of the POU factor Brn3a in aggressive neuroendocrine tumors. J Clin Endocrinol Metab 82:89–94[Abstract/Free Full Text]
  273. Therrien M, Drouin J 1991 Pituitary pro-opiomelanocortin gene expression requires synergistic interactions of several regulatory elements. Mol Cell Biol 11:3492–3503[Abstract/Free Full Text]
  274. Lombardi l Frigerio S, Collini P, Pilotti S 1997 Immunocytochemical and immunoelectron microscopical analysis of bcl2 expression in thyroid oxyphilic tumors. Ultrastruct Pathol 21:33–39[Medline]
  275. Sugawara A, Yen PM, Qi Y, Lechan RM, Chin WW 1995 Isoform-specific retinoid-X receptor (RXR) antibodies detect differential expression of RXR proteins in the pituitary gland. Endocrinology 136:1766–1774[Abstract]
  276. Feinberg AP, Vogelstein B 1983 Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92[CrossRef][Medline]
  277. Jones PA 1986 DNA methylation and cancer. Cancer Res 46:461–466[Free Full Text]
  278. Jones PA, Rideout III WM, Shen JC, Spruck CH, Tsai YC 1992 Methylation, mutation and cancer. Bioessays 14:33–36[CrossRef][Medline]
  279. Baylin SB, Makos M, Wu JJ, Yen RW, de Bustros A, Vertino P, Nelkin BD 1991 Abnormal patterns of DNA methylation in human neoplasia: potential consequences for tumor progression. Cancer Cells 3:383–390[Medline]
  280. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP 1998 Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141–196[Medline]
  281. Glenn CC, Driscoll DJ, Yang TP, Nicholls RD 1997 Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes. Mol Hum Reprod 3:321–332[Abstract/Free Full Text]
  282. Graff JR, Herman JG, Myohanen S, Baylin SB, Vertino PM 1997 Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation. J Biol Chem 272:22322–22329[Abstract/Free Full Text]
  283. Jones PA 1996 DNA methylation errors and cancer. Cancer Res 56:2463–2467[Free Full Text]
  284. Newell-Price JDC, Clark AJL 1997 The influence of DNA methylation on human proopiomelanocortin (POMC) gene expression in vitro and in normal and neoplastic tissue. J Endocrinol 155[Suppl 2]:OC19 (Abstract)
  285. Christofori G, Hanahan D 1994 Molecular dissection of multi-stage tumorigenesis in transgenic mice. Semin Cancer Biol 5:3–12[Medline]
  286. 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]
  287. Stenzel-Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W 1992 Development of Cushing’s syndrome in corticotropin-releasing factor transgenic mice. Endocrinology 130:3378–3386[Abstract/Free Full Text]
  288. Stenzel-Poore MP, Heinrichs SC, Rivest S, Koob GF, Vale WW 1994 Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J Neurosci 14:2579–2584[Abstract]
  289. Muglia L, Jacobson L, Dikkes P, Majzoub JA 1995 Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 373:427–432[CrossRef][Medline]
  290. Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee KF 1998 Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093–1102[CrossRef][Medline]
  291. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, Blanquet V, Steckler T, Holsboer F, Wurst W 1998 Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor. Nat Genet 19:162–166[CrossRef][Medline]



This article has been cited by other articles:


Home page
Eur J EndocrinolHome page
K. I Alexandraki, G. A Kaltsas, A. M Isidori, S. A Akker, W. M Drake, S. L Chew, J. P Monson, G M. Besser, and A. B Grossman
The prevalence and characteristic features of cyclicity and variability in Cushing's disease
Eur. J. Endocrinol., June 1, 2009; 160(6): 1011 - 1018.
[Abstract] [Full Text] [PDF]


Home page
J. Clin. Endocrinol. Metab.Home page
G. Assie, H. Bahurel, J. Coste, S. Silvera, M. Kujas, M.-A. Dugue, F. Karray, B. Dousset, J. Bertherat, P. Legmann, et al.
Corticotroph Tumor Progression after Adrenalectomy in Cushing's Disease: A Reappraisal of Nelson's Syndrome
J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 172 - 179.
[Abstract] [Full Text] [PDF]


Home page
EndocrinologyHome page
V. Castillo, D. Giacomini, M. Paez-Pereda, J. Stalla, M. Labeur, M. Theodoropoulou, F. Holsboer, A. B. Grossman, G. K. Stalla, and E. Arzt
Retinoic Acid as a Novel Medical Therapy for Cushing's Disease in Dogs
Endocrinology, September 1, 2006; 147(9): 4438 - 4444.
[Abstract] [Full Text] [PDF]


Home page
EndocrinologyHome page
T. Nigawara, Y. Iwasaki, M. Asai, M. Yoshida, M. Kambayashi, H. Sashinami, K. Hashimoto, and T. Suda
Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Eliminates Impaired Glucocorticoid Suppression and Induces Apoptosis in Corticotroph Tumor Cells
Endocrinology, February 1, 2006; 147(2): 769 - 772.
[Abstract] [Full Text] [PDF]


Home page
EndocrinologyHome page
D. Giacomini, M. Paez-Pereda, M. Theodoropoulou, M. Labeur, D. Refojo, J. Gerez, A. Chervin, S. Berner, M. Losa, M. Buchfelder, et al.
Bone Morphogenetic Protein-4 Inhibits Corticotroph Tumor Cells: Involvement in the Retinoic Acid Inhibitory Action
Endocrinology, January 1, 2006; 147(1): 247 - 256.
[Abstract] [Full Text] [PDF]


Home page
J. Clin. Endocrinol. Metab.Home page
G. Vila, M. Theodoropoulou, J. Stalla, J. C. Tonn, M. Losa, U. Renner, G. K. Stalla, and M. Paez-Pereda
Expression and Function of Sonic Hedgehog Pathway Components in Pituitary Adenomas: Evidence for a Direct Role in Hormone Secretion and Cell Proliferation
J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6687 - 6694.
[Abstract] [Full Text] [PDF]


Home page
J EndocrinolHome page
M Theodoropoulou, T Arzberger, Y Gruebler, M L Jaffrain-Rea, J Schlegel, L Schaaf, E Petrangeli, M Losa, G K Stalla, and U Pagotto
Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells
J. Endocrinol., November 1, 2004; 183(2): 385 - 394.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
D. J. Simpson, A. M. McNicol, D. C. Murray, A. Bahar, H. E. Turner, J. A. H. Wass, M. M. Esiri, R. N. Clayton, and W. E. Farrell
Molecular Pathology Shows p16 Methylation in Nonadenomatous Pituitaries from Patients with Cushing's Disease
Clin. Cancer Res., March 1, 2004; 10(5): 1780 - 1788.
[Abstract] [Full Text] [PDF]


Home page
J. Clin. Endocrinol. Metab.Home page
D. G. Morris, B. Kola, N. Borboli, G. A. Kaltsas, M. Gueorguiev, A. M. McNicol, R. Ferrier, T. H. Jones, S. Baldeweg, M. Powell, et al.
Identification of Adrenocorticotropin Receptor Messenger Ribonucleic Acid in the Human Pituitary and Its Loss of Expression in Pituitary Adenomas
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 6080 - 6087.
[Abstract] [Full Text] [PDF]


Home page
J. Clin. Endocrinol. Metab.Home page
A. M. Isidori, G. A. Kaltsas, S. Mohammed, D. G. Morris, P. Jenkins, S. L. Chew, J. P. Monson, G. M. Besser, and A. B. Grossman
Discriminatory Value of the Low-Dose Dexamethasone Suppression Test in Establishing the Diagnosis and Differential Diagnosis of Cushing's Syndrome
J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5299 - 5306.
[Abstract] [Full Text] [PDF]


Home page
EndocrinologyHome page
A. Spada and P. Beck-Peccoz
Editorial: New Strategy to Solve the Etiopathogenetic Conundrum of Pituitary Adenomas
Endocrinology, February 1, 2002; 143(2): 343 - 346.
[Full Text] [PDF]


Home page
J. Clin. Endocrinol. Metab.Home page
N. Hiroi, G. P. Chrousos, B. Kohn, A. Lafferty, M. Abu-Asab, S. Bonat, A. White, and S. R. Bornstein
Adrenocortical-Pituitary Hybrid Tumor Causing Cushing's Syndrome
J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2631 - 2637.
[Abstract] [Full Text] [PDF]


Home page
J. Clin. Endocrinol. Metab.Home page
M. Korbonits, I. Bujalska, M. Shimojo, J. Nobes, S. Jordan, A. B. Grossman, and P. M. Stewart
Expression of 11{beta}-Hydroxysteroid Dehydrogenase Isoenzymes in the Human Pituitary: Induction of the Type 2 Enzyme in Corticotropinomas and Other Pituitary Tumors
J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2728 - 2733.
[Abstract] [Full Text] [PDF]


Home page
J. Clin. Endocrinol. Metab.Home page
M. Moro, P. Putignano, M. Losa, C. Invitti, C. Maraschini, and F. Cavagnini
The Desmopressin Test in the Differential Diagnosis between Cushing's Disease and Pseudo-Cushing States
J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3569 - 3574.
[Abstract] [Full Text]


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dahia, P. L. M.
Right arrow Articles by Grossman, A. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dahia, P. L. M.
Right arrow Articles by Grossman, A. B.
Right arrowPubmed/NCBI databases
*Substance via MeSH


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals