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Clinical Endocrinology Branch (D.L., S.Y. J.-L. L.), and the Developmental Endocrinology Branch (C.B.), National Institutes of Health, Bethesda, Maryland 20892; and the Vollum Institute (A.B.), Oregon Health Sciences University, Portland, Oregon 97201
| Abstract |
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I. Introduction
II. Original Somatomedin Hypothesis
III. The Alternative or "Revised" Somatomedin Hypothesis
A. Dual effector theory
B. Recent evidence questioning the dual effector theory
IV. GH and the GH Receptor (GHR)
A. GH
B. The GHR and GHR signal transduction
C. The physiological effects of GH
D. GH actions not mediated by IGF-I
V. The IGF System
A. IGF-I and the IGF-I receptor
B. Insulin-like growth factor binding proteins
C. Physiological effects of IGFs
D. IGF-Is role in the cell cycle
VI. Transgenic Tools for Analyzing the Somatotropic Axis
A. Transgenic mice overexpressing GH or IGF-I
B. Targeted deletion of the IGF system
C. New approaches: conditional knockouts using the Cre-loxP system provide new insights into the function of circulating IGF-I
VII. Conclusions and Future Directions
A. Current understanding of the somatotropic axis
B. What is the function of circulating IGF?
| I. Introduction |
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| II. Original Somatomedin Hypothesis |
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Subsequent experiments provided further evidence that the effect of GH on cartilage growth was indirect. Serum from hypophysectomized rats treated with bGH, but not bGH itself, could stimulate DNA synthesis, as measured by 3H-thymidine incorporation into cartilage (13). Furthermore, the mitogenic effects of bGH could be mimicked by a partially purified fraction of "sulfation factor," derived from the serum of patients with acromegaly, which is associated with elevated circulating GH levels. The term "somatomedin" was coined to reflect the ability of the substance to mediate the effects of GH (also referred to as "somatotropin") (14). The somatomedins were subdivided into subtypes, with somatomedin C later identified as the GH-responsive form.
Two decades (1978) after the existence of somatomedin(s) had first been
postulated, IGF-I and IGF-II were purified and characterized. IGF-I was
shown to be the somatomedin substance that was regulated by circulating
GH in rats (15, 16). Both substances were termed "insulin-like,"
because of their ability to stimulate glucose uptake into fat cells and
muscle (17). Thus, it was perhaps not surprising that their sequence
and tertiary structure were similar to those of proinsulin. Both IGF-I
and IGF-II share approximately 50% amino acid identity with insulin.
The major structural difference between the IGFs and insulin is that
the IGFs retain the C chain that is cleaved from proinsulin, and there
is a small D extension to the A chain in the IGF molecules (16, 18, 19). While the structural similarity between insulin and IGF-I
suggested a metabolic function, the belief predominated that the
primary functional role of the IGFs was to act as growth factors. At
this stage, the original somatomedin hypothesis remained the most
widely accepted model of IGF action. This hypothesis put forward that
growth is determined by GH acting primarily on the liver, where it
stimulates IGF-I synthesis and release. IGF-I then circulates to the
main target organs, such as cartilage and bones, and thus acts in an
endocrine mode (Fig. 1A
). Circulating
IGF-I also provides a feedback effect within the somatotropic axis,
with circulating IGF-I suppressing the further release of GH from the
pituitary (20). A model whereby the hypothalamic-pituitary-liver axis
controlled growth was attractive and certainly seemed to fit the models
of other hypothalamic-pituitary axes of the time. However, subsequent
experiments and findings have required an expansion of this hypothesis,
in view of new evidence showing that IGF-I synthesis occurs in many
tissues and is often regulated by a variety of local and endocrine
factors.
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| III. The Alternative or "Revised" Somatomedin Hypothesis |
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Isaksson and co-workers (30) raised further questions about whether circulating IGF-I plays a role in mediating the actions of GH. Their studies demonstrated that direct injection of hGH into the cartilage growth plate of the hind limbs of hypophysectomized rats at days 14, 16, and 19 of age resulted in a significant increase in longitudinal bone growth. The contralateral limb, which received no hGH, did not show a significant increase in growth rate, indicating that the effect was local (30). They concluded that the circulating form of IGF-I is not required for stimulation of longitudinal bone growth, but rather that GH itself directly stimulates the cartilage. These authors raised the possibility that the effect of GH was mediated by local production of IGF-I. This concept was supported by other investigators who infused rat hindlimb arteries with rat GH or human IGF-I and observed increased growth of epiphyseal plates (31, 32). These results strongly indicated that GH has local effects that may be independent of the increase in the circulating "endocrine" form of IGF-I, thereby introducing an alternative to the original somatomedin hypothesis. Isaksson and co-workers (33, 34) postulated that GH was capable of stimulating the differentiation of epiphyseal growth plate precursor cells both directly and indirectly, by increasing their responsiveness to IGF-I. Furthermore, GH enhances the local production of IGF-I that, in turn, stimulates the clonal expansion of differentiating chondrocytes.
How can the earlier findings of Salmon and Daughaday, which suggested an endocrine role for IGF-I, and the more recent findings, which suggest an autocrine/paracrine role, be reconciled? The alternative somatomedin hypothesis could be viewed as a compromise, where both circulating "endocrine" IGF-I and locally produced IGF-I are responsive to GH and responsible for the effects of GH. In addition, the possibility that GH may have IGF-I-independent effects on tissues could not be excluded.
A. Dual effector theory
In 1985, Green and co-workers (35) proposed a new concept
concerning the roles that GH and IGF-I play in growth and
differentiation known as the "dual effector hypothesis." The dual
effector hypothesis suggests that GH stimulates the specific
differentiation of adipocytes, while IGF-I stimulates their clonal
expansion (Fig. 1B
). Their proposal was based on studies from the 1970s
where several fibroblast-like cell lines were used as models for
studying adipocyte differentiation, including 3T3-L1, BALB 3T3-T, and
ST 13 cells that were obtained from Swiss 3T3 and BALB 3T3 whole mouse
embryos (36, 37, 38). The adipocyte phenotype appears in these cells upon
growth arrest once they reach confluence. As they convert to
adipocytes, there is a marked increase in expression in insulin
receptors, from approximately 7,000 receptors per cell to 250,000
insulin receptors per cell. The marked increase in insulin receptor
number is associated with an increased sensitivity and responsiveness
to insulin as shown by increased glucose uptake, lipid synthesis, and
glucose oxidation (39, 40, 41, 42). In parallel, IGF-I receptors, which are
expressed at high levels in preadipocytes, are markedly reduced in the
differentiated adipocyte. At this time, the differentiation, but not
the growth, of 3T3 preadipocytes was found to be dependent on a serum
"adipogenic factor." A hormone(s) secreted from the pituitary was
considered a possible candidate by Morikawa et al. (43),
since pituitary extracts and recombinant human GH showed this activity,
while serum from hypophysectomized rats showed reduced activity. Thus,
as opposed to the original concept that IGF-I mediated all
the functions of GH, they showed that preadipocytes could be induced to
differentiate into adipocytes by GH (44). Furthermore, since
somatomedins could not replace GH in their studies, they suggested that
IGF-I induced clonal expansion of these differentiated cells (45). By
analogy with the adipocyte work of Greene et al., the
Isaakson group extended the "dual effector" theory to the growth
plate, proposing that GH acts directly at the growth plate germinal
zone to stimulate the differentiation of chondrocytes. GH also acts to
induce local IGF-I synthesis, which was thought to stimulate the clonal
expansion of chondrocyte columns in an autocrine/paracrine manner (the
body of work bearing on this hypothesis was reviewed in Refs. 33, 46).
B. Recent evidence questioning the dual effector theory
The evidence upon which the dual effector hypothesis of how GH and
IGF-I interact to regulate growth may well be flawed. It was
subsequently clearly shown that insulin at high doses and IGF-I at
physiological concentrations also cause preadipocytes to differentiate
into mature adipocytes (41, 42, 47, 48) probably by activating the
IGF-I receptors. However, the 3T3-F442A cell line (a subclone of mouse
3T3 cells that has the unusual property of undergoing adipogenesis) has
been studied extensively as a model of IGF-I-independent
differentiation by GH and has been valuable in elucidating the
molecular mechanisms of GH action such as identifying specific
activation of transcription factors such as Elk-1 and Sap-1a (49).
More recent studies have yielded data that are not consistent with the dual effector hypothesis. The suggestion that GH has direct, non-IGF-I-dependent effects on growth plate germinal zone cells has been confirmed in studies showing that GH stimulates increased proliferation of germinal zone cells (50, 51). While IGF-I was also shown to have this effect (51), the growth plate germinal zones are significantly expanded in igf-I null mice (52). Given the complete absence of IGF-I in these mice, it is inferred that elevated endogenous GH levels are responsible for this germinal zone effect. It remains to be determined whether GHs effect on the germinal zone may be mediated by local IGF-II production.
While the hypothesis that GH has direct, non-IGF-Idependent effects on growth plate germinal cells has been adequately confirmed, the further suggestion that GH induces IGF-I synthesis in proliferative chondrocytes in vivo (33) is disputed. For example, both Shinar et al. (53) and Wang et al. (54) were unable to detect IGF-I mRNA in growth plate chondrocytes of rats or mice of any age, while both groups found abundant IGF-II mRNA in proliferative chondrocytes of both murine species. The finding of IGF-I mRNA and immunoreactivity in growth plate chondrocytes could be explained by cross-reactivity of IGF-I probes with IGF-II, or perhaps by strain-specific differences in local IGF expression. We have noted significant variability in local patterns of IGF-I expression between rats and mice and even between different strains of rats and mice (Ref. 55 and J. Zhou and C. A. Bondy, unpublished data).
Despite the continuing uncertainty about its mode of action, IGF-I clearly has an important role in longitudinal bone growth, since igf-I gene deletion results in dwarfism in mice (56, 57) and extreme short stature in humans (58). Analysis of long bone growth and growth plate characteristics in igf-I null mice has shown that growth plate chondrocyte numbers and proliferation are normal, despite a 35% reduction in the rate of long bone growth (52). Chondrocytes from igf-I null mice are, however, smaller than wild type at all levels of the growth plate. The terminal hypertrophic chondrocytes, which form the scaffold upon which linear growth extends, are reduced in linear dimension by 30%, accounting for most of the decreased longitudinal growth in igf-I null mice. Expression of the insulin-sensitive glucose transporter, GLUT4, is decreased, glycogen synthase kinase 3b is hypophosphorylated, glycogen stores are depleted, and ribosomal RNA levels are drastically reduced in igf-I null chondrocytes (52).
The data derived from examination of igf-I null mice suggest
that IGF-Is role in longitudinal bone growth involves
"insulin-like" anabolic actions that augment chondrocyte
hypertrophy, rather than mitogenic effects on chondrocytes, as
previously thought. The fact that IGF-II, rather than IGF-I, is
normally expressed by proliferative chondrocytes (53, 54) and that
IGF-II expression is not impaired by IGF-I deletion may explain the
normal proliferation in the igf-I null growth plate. A new
view of GH and IGF interactions in long bone growth at the level of the
growth plate is illustrated in Fig. 2
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The source of IGF-I that promotes chondrocyte hypertrophy remains
uncertain. IGF-I mRNA is concentrated in the murine periosteum and
perichondrium (53, 54) and is also expressed by muscle and fat cells;
therefore, local tissue sources may provide enough IGF-I effect to
enhance longitudinal bone growth. Certainly, circulating IGF-I derived
from the liver may also serve this role.
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| IV. GH and the GH Receptor (GHR) |
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The "somatotropic axis" was originally described as being comprised of the hypothalamus, pituitary, and liver. The hypothalamus was thought to be the "control center," regulating the secretion of GH from the pituitary (74). While concepts of IGF function have evolved to accommodate new data, the basic concepts concerning central regulation of GH secretion have remained largely unchanged. Two hypothalamic factors, GH releasing hormone (GHRH) (75, 76) and the inhibitory hormone, somatostatin (SS) (77), act in concert to regulate GH secretion from pituitary somatotrophs.
Several new factors controlling GH release and novel pathways that regulate GH secretion have recently been reported (78, 79). These factors are primarily related to or derived from the metabolic status of the organism, which is consistent with the role of GH in regulating metabolism, as well as growth. FFA act directly on the pituitary to inhibit GH release, which is postulated to complete a feedback loop, since GH stimulates lipid mobilization (80, 81). The adipostat hormone leptin stimulates GH secretion at the level of the hypothalamus by regulating GHRH and SS activity (82, 83, 84). The effect of leptin on GH secretion may also involve neuropeptide Y (NPY), since leptin suppresses NPY expression, and infusion of NPY is known to suppress GH secretion (85, 86).
Another GH-secretory factor that is derived from a peripheral organ has recently been isolated. A synthetic hexapeptide, hexarelin, has long shown promise as an orally active GH secretagogue (87). Hexarelin belongs to a family of GH-releasing peptides (e.g., GHRP-1, GHRP-2, GHRP-6) with demonstrable GH secretagogue activity (88). A G protein-coupled receptor expressed in the pituitary and activated by the small synthetic GH secretagogues (GHS-R) was cloned in 1996 (79). The cloned receptor was recently used to isolate Ghrelin, a 28-residue peptide, from stomach extracts (89). Ghrelin mRNA and immunoreactivity were found to be expressed at high levels in endocrine cells of the stomach, in addition to lower levels of expression of the hypothalamic arcuate nucleus. Ghrelin circulates at a considerable plasma concentration, in the order of 120 fmol/ml, suggesting that GH secretion is controlled by both hypothalamic (i.e., neuroendocrine) and peripheral signals.
B. The GHR and GHR signal transduction
The actions of GH are mediated by the binding of GH to the
transmembrane GHR, which is present on the surface of most cells. The
GHR was the first member of the type I cytokine receptor family to be
cloned, and all members share the same single-transmembrane domain
structure. This family includes the closely related PRL receptor, as
well as several of the interleukin and colony-stimulating factor
receptors (67).
The GHR is subject to a number of posttranscriptional and posttranslational modifications during synthesis. The most significant of these is the generation of a soluble GH binding protein (GHBP), comprised of the GHR extracellular ligand-binding domain (90, 91). The mechanism used to generate the soluble GHBP varies across species. The nascent GHR mRNA in rodents was the first discovered to undergo alternate splicing of the nascent RNA transcript producing a truncated form (92), while GHBP from other species was originally believed to result from proteolytic cleavage of the full-length receptor (93, 94). It is generally believed that the primary function of the GHBP is to act as a physiological buffer, stabilizing GH in plasma; however, there is still no consensus as to what the physiological functions of truncated GHR isoform are (95, 96, 97).
As with most cytokine receptors, the GHR utilizes the JAK-STAT signal
transduction pathway (98) (Fig. 3
). The activated GHR
associates with JAK2 (janus kinase 2). JAK2 is a tyrosine kinase, which
upon activation by GH phosphorylates STATs-1, -3, -5a, and -5b (signal
transducers and activators of transcription) on tyrosines (98). Upon
phosphorylation by GHR and JAK2, the STAT proteins translocate to the
nucleus where they bind to specific DNA sequences and activate gene
transcription (99, 100). The current evidence suggests that the STAT
proteins are involved in programming the different effects observed in
response to pulsatile or continuous activation of the GHR by GH. STAT
5b is believed to be responsible for regulating gene expression in the
adult male liver in response to the male-specific pulsatile pattern of
GH secretion (101).
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GH has also been shown to induce increased influx of extracellular calcium via the plasma membrane voltagedependent L-type calcium channels (105). This elevation of intracellular calcium is necessary for GH-induced transactivation of the Spi 2.1 promoter. GH-induced calcium influx may also be the proximal cause underlying the refractoriness to the effects of further GH exposure on lipogenesis and glucose uptake, the elevated intracellular Ca concentration causing the refractoriness (106, 107). GH may also increase intracellular diacylglycerol, which potently activates protein kinase C (PKC). This is associated with the generation of inositol triphosphate (IP3), suggesting that GH may stimulate a pathway involving either phosphoinositide hydrolysis [leading to IP3 accumulation followed by diacylglycerol (DAG) generation] or phosphatidylcholine breakdown, which can lead to DAG generation directly). Activation of PKC by GH results in activation of MAP kinases, p90rsk, and induction of c-fos (108, 109, 110).
GH stimulation has been shown to regulate gene expression of IGF-I and many of the IGF-binding proteins (IGFBPs). However, only the promoter for the acid labile subunit (ALS) of the IGFBP-3 complex has an identifiable GH-responsive element (111). Interestingly, in situ hybridization studies show that the mRNAs encoding IGF-I, IGFBP-3, and ALS are not colocalized within the same cells in the liver (112). Hepatocytes express mRNAs encoding IGF-I and ALS, whereas IGFBP-3 mRNA is exclusively expressed in adjacent endothelial cells of the hepatic sinusoids. Unlike hepatocytes, sinusoidal endothelial cells of the liver do not express detectable levels of GHR mRNA. Thus, the regulation of IGFBP-3 levels by GH is presumably indirect and most likely to be mediated by IGF-I, at least in rodents, as demonstrated by the marked reduction in circulating IGFBP-3 levels in liver-specific IGF-I gene-deleted mice despite elevated GH levels. Administration of rhIGF-I reversed this effect (Yakar et al., manuscript submitted). Conversely, hepatocytes do not express detectable levels of IGF-I receptor mRNA. Thus, IGF-I presumably does not act on hepatocytes directly, but rather relies on the inhibition of GH to complete a feedback circuit. Alternatively, IGF-I may affect IGFBP-3 levels by a posttranslational event that may include stabilization of the protein and protection against proteases.
C. The physiological effects of GH
The physiological actions of GH are pleiotropic and involve
multiple organs and physiological systems (Table 1
). GH exerts many metabolic effects that
persist throughout life. GH is essentially an anabolic hormone,
inducing positive nitrogen balance and protein synthesis in muscle
(113). Muscle size is increased in GH-deficient individuals undergoing
replacement therapy with recombinant human GH (rhGH) at all ages (114, 115). Because GH enhances amino acid uptake into skeletal muscle, it
has been suggested that this tissue is the primary target of the
physiological effects of GH (116, 117). However, conflicting reports
have suggested that other tissues may be equally important in the
effect of GH on nitrogen balance. Furthermore, it remains controversial
whether the effects of GH on nitrogen balance are direct or mediated by
IGF-I (118).
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Systemic administration of GH stimulates longitudinal bone growth and
skeletal muscle growth, whereas treatment with IGF-I increases the size
of lymphoid tissues (spleen and thymus) and kidney (122). GH has a more
robust effect than IGF-I on longitudinal bone growth in animals, and
the effects of these factors may be additive (123, 124, 125). However, many
studies have shown a greater effect of rhGH administration compared
with rhIGF-I administration (126), and these results need to be
interpreted carefully. GH administration systemically increases
circulating levels of IGF-I, IGFBP-3, and ALS (Fig. 1C
1). IGF-I
administration, on the other hand, while transiently increasing
circulating levels of IGF-I, inhibits GH secretion and may actually
decrease IGFBP-3 and ALS levels, thereby leading to faster clearance of
IGF-I from the circulation. Indeed, this has led investigators to begin
clinical trials using a complex of IGF-I/IGFBP-3, rather than IGF-I
alone. In hypophysectomized rats, the coadministration of IGFBP-3 with
IGF-I markedly reduced the hypoglycemia associated with IGF-I treatment
(127). The effects of coadministration of IGFBP-3 on the anabolic
actions of IGF-I were variable, however, either showing no change or
enhancing the effects of IGF-I on growth (127).
Evidence for synthesis of GH in a number of extrapituitary sites,
including the lateral hypothalamus (128), lymphocytes, thymocytes
(129), neutrophils (130), the placenta (131), and both normal and
neoplastic mammary tissue (132), has been reported. These findings
suggest that GH may have local paracrine/autocrine effects that might
be distinct from, or in addition to, its classic effects that are known
to be mediated by circulating IGF-I. These local paracrine/autocrine
effects may be mediated either by local production of IGF-I or by other
additional factors (49) (Table 2
).
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GH has a lipolytic action on fat and muscle, whereby circulating FFA and glycerol levels rise after acute administration of GH. This effect is apparently mediated by the inhibition of lipoprotein lipase, an enzyme involved in lipid accumulation in adipocytes (137, 138), and represents a major effect of GH on metabolic intermediates. Long-term effects of GH are decreased deposition of fat and increased fat mobilization. GH administration also causes mild reductions in low-density lipoprotein (LDL) cholesterol levels and small elevations in high-density lipoprotein (HDL) cholesterol (139). Acute administration of GH to fat and other tissue explants causes a temporary insulin-like effect on glucose uptake. In contrast, chronic exposure to GH leads to insulin resistance associated with hyperinsulinemia that is primarily due to a post receptor defect in insulin signaling (140). The acute insulin-like activity of GH on carbohydrate metabolism seen both in vivo and in vitro appears to be independent of both IGF-I and insulin, since these effects have also been observed in isolated tissue preparations and in cultured cells (141). While the exact mechanism(s) are not yet well defined, GH-induced tyrosine phosphorylation of IRS-1 and/or IRS-2 may be involved (103). Prolonged GH stimulation ultimately results in hyperglycemia that is associated with enhanced hepatic gluconeogenesis and glycogenolysis. These effects may be indirectly caused by the GH-induced lipolysis and elevated plasma FFA that inhibit insulin activity at its target tissues. This so-called "lipotoxic" effect was first noted by Randle and others (142), and became known as the glucose/fatty acid or Randle cycle.
D. GH actions not mediated by IGF-I
The strongest evidence for a growth-promoting effect of GH that is
independent of IGF-I has come from the observation that growth plate
germinal zones are significantly expanded in igf-I null mice
(Fig. 2
) (52). GH treatment also induces hepatomegaly in
igf-I null mice (143). Furthermore, IGF-I is not the only
growth factor regulated by GH (Table 2
). After partial hepatectomy in
rats, GH induces expression of the hepatocyte growth factor gene in
liver (144). GH also modulates basic fibroblast growth factor gene
expression in costal cartilage. In addition, GH regulates epidermal
growth factor (EGF) and EGF receptor gene expression in kidney and
liver (145), respectively. GH also increases levels of estrogen
receptors in the uterus of guinea pigs (146). Bone morphogenetic
proteins (BMPs) play important roles in the differentiation of multiple
tissues. Both GH and IGF-I increase the expression of BMP-2 and -4.
However, GH induces the expression of these genes even in the presence
of an anti-IGF-I neutralizing antibody, suggesting that this effect of
GH may also be independent of IGF-I (147). Similar results were
obtained for when the effects of GH on colony formation of rabbit
epiphyseal chondrocytes (148) and ß-cell proliferation (149) were
evaluated.
| V. The IGF System |
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The IGF-I receptor and insulin receptor are very similar in structure
and show approximately 60% identity overall at the amino acid level
(155). However, certain regions of these receptors share very high
degrees of homology, including the tyrosine kinase domain, which shows
about 85% homology between the two receptors. Both receptors are
comprised of
- and ß-subunits with the
-subunit localized
entirely extracellularly and the ß-subunit spanning the membrane and
localized primarily intracellularly (156). The receptors assemble a
2ß2-configuration with
ligand binding being primarily mediated by the
-subunits, which form
a binding pocket. The intracellular domains of the ß-subunits contain
the tyrosine kinase activity and tyrosine residues that become
phosphorylated upon activation of the receptor (157).
Upon tyrosine phosphorylation of the IGF-I receptor, multiple
endogenous substrates are recruited to "docking sites" formed by
the phosphotyrosine residues (Fig. 4
)(2).
These include the IRS family of proteins (IRS-1 through -4), which
associate with the IGF-I receptor through PTB (phosphotyrosine binding)
domains and, like the SHC family of adapter proteins, with SH2
domains (158, 159). Both these docking proteins bind to the IGF-I
receptor at the juxtamembrane region through the NPXpY motif (160, 161). These docking proteins are then able to recruit other substrates
that lead to activation of a number of essential signaling cascades.
These include SH2 domain-containing proteins, which bind to specific
motifs that contain phosphotyrosine. For example, the p85 subunit of
PI3'-K, an enzyme that phosphorylates intracellular lipids, binds to
pYXXM motifs on the IRS molecules (162). Grb2 (growth factor receptor
binding protein-2) binds to pYVNM motifs (163), whereas SHP-2 (a
protein-tyrosine phosphatase) and phospholipase C
bind to pYIEV
motifs within IRS molecules (159). SHC, on the other hand, apparently
only binds Grb2. Recruitment of SHC to the activated receptor leads to
a cascade of events involving association of SHC with Grb2, association
of Grb2 with mSOS (a nucleotide exchange protein), activation of Ras (a
small monomeric G protein) by mSOS, and ultimately, activation of the
MAP kinase signaling pathway (164, 165). While the IRS proteins are
also capable of recruiting Grb2, they apparently play a more prominent
role in activation of the PI3'-K pathway. This pathway leads to
activation of Akt kinases and p70S6 kinase (166).
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C. Physiological effects of IGFs
IGF-I plays an important role in both embryonic and postnatal
growth. Mice carrying null mutations in the IGF-I gene are born small
and grow very poorly postnatally (57, 154, 171). Since GH and GHR
gene-deleted mice have relatively normal birth weights, this strongly
supports a GH-independent effect of IGF-I in embryonic growth.
Moreover, plasma IGF-I levels in humans correlate with body size.
Constitutional tall children have elevated plasma IGF-I levels (172),
whereas lines of mice selected for high IGF-I levels show increased
body weight (173). Infusions of rhIGF-I also enhance body weight and
size in a number of models, further suggesting a role for circulating
IGF-I in growth. Often, injections of GH have been shown to be more
effective in promoting growth, at least in bone, whereas IGF-I was more
effective on kidney and spleen (122). These data may be interpreted to
suggest that IGF-I may function alone in certain tissues, whereas it
may mediate the effects of GH in other tissues (Table 3
). IGF-Is role in ovarian follicular
development and uterine growth is independent of GH, since GHR
gene-deleted mice are fertile, whereas IGF-I gene-deleted mice are not
(174). Furthermore, GH-resistant dwarfs are fertile (175). Since GH
also increases the levels of certain IGFBPs, the higher potency of GH,
relative to IGF-I, might be due to the fact that GH simultaneously
stimulates the synthesis of IGF-I and produces a microenvironment that
facilitates IGF-I action through modification of the IGFBP profile.
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In light of its insulin-like effects, rhIGF-I has been used successfully as an adjuvant to insulin therapy in patients with type 1 and type 2 diabetes. Plasma glucose concentrations fall after acute or chronic administration of rhIGF-I. This can be observed in those patients who are also insulin resistant (181, 182, 183). This effect of rhIGF-I is in direct contrast to GH therapy, which leads to increased insulin resistance. In type 1 patients with poorly controlled diabetes, levels of circulating IGF-I are reduced and GH levels are elevated. Administration of rhIGF-I often restores the high levels of GH to normal, leading to improved insulin sensitivity, and enhanced glucose uptake in peripheral tissues (184). In type 2 diabetic patients, who are commonly insulin-resistant, IGF-I therapy leads to some improvement, which is primarily due to enhanced muscle glucose uptake (185, 186, 187, 188). Whether this effect is mediated by the IGF-I receptor, the insulin receptor, or hybrid receptors expressed in muscle remains to be determined (178, 189). Nevertheless, these data once again illustrate the distinct physiological effects of GH and IGF-I.
D. IGF-Is role in the cell cycle
It is worth noting that IGF-Is original growth-promoting
activity was characterized in terms of protein synthesis ("sulfation
factor," see above). The view of IGF-I as a mitogen was derived
largely from in vitro studies of growth-arrested fibroblast
cell lines [reviewed by Pardee (190)]. These in vitro
studies established the view that growth factors act primarily in the
G1 phase of the cell cycle. Peptides such as
PDGF, FGF, and EGF, termed "competence factors," stimulated
quiescent cells to enter G1, while IGF-I spurred
progression through G1 to S-phase and therefore
was deemed a "G1-progression factor" (191).
More recent studies using IGF-I and IGF-I receptor "knockout"
models suggest the situation is more complicated. Rubin and Baserga
(192) investigated cell cycle kinetics in fibroblasts derived from
Igf1r null embryos and found that these cells demonstrate a
G2/M phase duration 4-fold longer than comparable
wild-type cells, while G1 is not blocked but is
doubled in duration. Moreover, progression through
G1 and S-phases is normal in the intact
Igf1 null animal, indicating that IGF-I has a minor, if any,
role as a G1 progression factor in
vivo (193). However, Igf1 null cells are profoundly
retarded in their transit through G2/M, at least
in the estradiol-stimulated uterus (193), suggesting that IGF-I may be
required for timely progression through later phases of the cell cycle.
On the other hand, IGF-II is capable of diminishing the
G1 checkpoint after DNA damage (194). Further
studies will undoubtedly resolve these important issues.
| VI. Transgenic Tools for Analyzing the Somatotropic Axis |
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Starting about 3 weeks postnatally, the growth rate of transgenic mice expressing the hGH gene accelerate such that the final weight of hGH transgenics is about twice that observed in normal littermates (133). Interestingly, this doubling in size corresponds more closely with the 2-fold increase in circulating IGF-I levels than with the greater elevations in circulating GH levels (199, 200). While these data were initially interpreted as being consistent with the somatomedin hypothesis, they are equally consistent with the alternative somatomedin hypothesis, i.e., whereas postnatal growth by GH is IGF-I dependent, the GH effect can be mediated by either endocrine (circulating) or paracrine (locally produced) derived IGF-I.
More recent studies, comparing transgenic mice overexpressing GH to
those overexpressing IGF-I, have yielded interesting results. Mice
overexpressing the IGF-I gene demonstrated a small but significant
(
1.4 fold) increase in body weight, starting at about 2 months
postnatally (199, 200). The weight increase was due to hyperplasia in a
number of organs. There was, however, no increase in bone length or
bone accumulation. Circulating GH levels were markedly reduced in these
mice. Thus, on the basis of these results, one could speculate that
bone growth requires concomitant elevation in both GH and IGF-I levels.
Paradoxically, in another model where GH-deficient mice were crossed
with IGF-I overexpressing transgenic mice, the resultant offspring
exhibited increased organ and bone growth (201). Thus, it is possible
that in the absence of GH, excess IGF-I may fully compensate for the
lack of GH at the level of the target tissue. Furthermore, this study
provides additional evidence against the dual effector hypothesis (33, 46).
B. Targeted deletion of the IGF system
Naturally occurring mutations in the IGF system have proved
to be extremely rare. A single patient with both intrauterine and
postnatal growth retardation has been found who has a deletion of the
IGF-I gene (58). Since the low levels of circulating IGF-I are
associated with elevated GH levels, this strongly supports the
somatomedin hypothesis (that IGF-I is a major mediator of GH-induced
postnatal growth). Furthermore, since both the human and murine
igf1 deletions demonstrate growth retardation in
utero, before the ontogeny of normal GH expression, and more
severe growth retardation in toto than GH or GHR mutants, it
appears that IGF-I has extensive GH-independent growth-promoting
effects. Indirect evidence that has been used to refute the original
somatomedin hypothesis and support the revised hypothesis is the
finding that GH-resistant (Laron-type) dwarfs do not respond to rhIGF-I
therapy with "catch-up growth" nearly as well as GH-deficient
children in response to rhGH therapy (202). These findings might
support the notion that there are important paracrine effects of IGF-I
that are somewhat GH dependent, but they may also reflect the
inadequate maintenance of circulating IGF-I levels in the absence of
GH-induced mobilization of the ternary complex (Fig. 1C
).
Efstratiadis and colleagues (56, 154) used standard gene targeting technologies to create lines of mice lacking the igf1, igf2, igf1r and igf2r genes. These studies provided critical information regarding the roles of the IGF system during development, while also providing surprising data regarding the possibility of another receptor mediating the effects of IGF-II on fetal growth. Subsequent observations of GH- and IGF-I-deficient humans and mice have shown that the specific suggestions of the original dual effector schemes do not hold up (e.g., that GH is required for adipocyte or chondrocyte differentiation). However, the concept that GH may have both direct and indirect growth-promoting effects is still viable. If, however, GH had major, IGF-I-independent growth-promoting effects, one would expect that the GHR knockout mouse would be smaller than the IGF-I knockout. However, the reverse is true (174), which is more consistent with IGF-I having effects on fetal and early neonatal growth that are independent of GH.
To further study the relationship between IGF-I and GH actions in vivo, we analyzed GH action in IGF-I knockout mice (171). The IGF-I null mice were generated by crossing mice in which exon 4 of the IGF-I gene is flanked by tandem repeats of the lox/P sequences with a line of mice expressing Cre (recombinase) driven by the EIIa promoter. The EIIa promoter is expressed at the early blastocyst stages of development and theoretically should cause recombination of the loxP-flanked allele. (An overview of the Cre/lox approach for gene targeting studies is discussed in more detail in Section C, below). Southern blot analysis revealed that the offspring of these crosses indeed demonstrated recombination of the IGF-I alleles. Homozygous animals failed to express detectable IGF-I mRNA in all tissues studied. Total deletion of the IGF-I gene was confirmed by separating IGF-I from its binding proteins by HPLC followed by measuring circulating IGF-I levels by a sensitive RIA technique. Using this approach, IGF-I was not detectable in the serum of IGF-I null mice at 6 weeks of age. Pups with homozygous deletions of the IGF-I gene were born at approximately 60% of the body weight of their normal littermates, suggesting a role for IGF-I in prenatal growth and development. However, their postnatal growth and development were even more markedly affected by the absence of IGF-I. At 78 weeks of age, these animals were only about 30% the weight of their normal littermates, and adults were infertile. These results were very similar to those described previously by Efstratiadis (56, 154) and Powell-Braxton et al. (57) using the traditional knockout approach.
Homozygous IGF-I-deficient mice were injected with rhGH (3 mg/kg
subcutaneously, twice daily) from postnatal day 14 to day 56. Control
animals received the diluent alone. Direct comparisons were made to
wild-type littermates that received either rhGH or diluent over the
same period. While GH injections significantly enhanced the growth of
wild-type mice by 20%, as measured by body weight, in wild-type mice
(from
20 g to
24 g), GH had no effect on growth in the
IGF-I-deficient animals. Body length was similarly increased in the
wild-type mice receiving rhGH but unchanged in the IGF-I-deficient
mice. rhGH appeared to be active in the IGF-I-deficient mice, as these
animals exhibited an increase in liver weight from approximately 7
g to about 8 g, as well as increases in junB mRNA
levels in the liver (143). Circulating GH levels were markedly elevated
in the IGF-I-deficient mice (75 ng/ml vs. 6 ng/ml in the
wild-type animals). Despite this dramatic elevation in circulating GH
levels, and the administration of exogenous rhGH, there was no
significant effect of GH on overall body growth or development in these
animals. Thus, at least in mice, postnatal growth is dependent on
IGF-I. While this may be true of overall body growth and development,
this does not exclude the possibility that other effects of GH, such as
liver growth (see below), are IGF-I independent, and probably occur at
a local tissue level. Furthermore, these studies do not distinguish
between the role of circulating IGF-I and local autocrine/paracrine
forms of IGF-I, since the synthesis of both liver IGF-I and that
expressed by some extrahepatic tissues such as bone are GH-dependent
(26).
C. New approaches: conditional knockouts using the Cre-loxP system
provide new insights into the function of circulating IGF-I
In recent years, in vivo gene targeting studies have
enabled us to study the function of specific genes in the whole animal.
However, a common criticism of this experimental approach is that
disruption of a gene that is critical for normal development may
prohibit using the resulting animals as an appropriate model to study
normal function of the gene in the adult. Furthermore, it is possible
that compensatory mechanisms, e.g., the up-regulation of
another gene with a similar function, may obscure the loss of function
of the gene of interest. Thus, the ability to inactivate genes in a
tissue and temporally regulated manner represents an incredibly
powerful new tool to the molecular biologist. Genes may be excised from
the genome utilizing a site-specific recombination technology adapted
from bacteriophage. Bacteriophage P1 Cre recombinase, a 38-kDa protein,
recognizes 34-bp DNA sequences called loxP sites (locus of cross-over
P1) (203, 204). When the loxP sites are in tandem and flanking an
essential exon of the gene of interest, Cre induces an intramolecular
recombination and excision of the intervening DNA, resulting in
deletion of the exon (Fig. 5
). By placing
the Cre recombinase under the control of tissue-specific or inducible
promoters, the function of a gene in a certain tissue(s) can be
examined in the absence of potentially critical developmental
abnormalities. The approach is technically quite challenging, however,
requiring the generation by homologous recombination in ES cells of the
gene of interest flanked with loxP sequences and different lines of
mice expressing Cre under the control of the desired promoter for
tissue-specific Cre expression. This procedure is further complicated
when the level of Cre recombinase expression is insufficient to achieve
complete abrogation of gene function. Mice with a gene flanked by loxP
sites therefore represent an extremely valuable resource.
|
Exon 4 encodes amino acid residues 2670 of the IGF-I peptide, including part of the B domain and the entire C, A, and D domains. This region of the peptide is solely responsible for IGF-I binding to its cognate receptor (IGF-I receptor) and has been previously targeted by others to create a total IGF-I knockout for developmental studies (154).
To create a liver-specific deletion of the IGF-I gene, we generated transgenic mice expressing Cre recombinase exclusively in the liver, by expressing Cre under the control of the albumin promoter. The albumin promoter is highly active in the liver and weakly active in certain other tissues. The albumin gene is activated late during fetal development, becoming easily detectable at about 10 days postnatally, with maximal expression levels occurring during the adult stages of development (205). Cross-breeding of the loxP-flanked IGF-I mice and the albumin-Cre expressing mice resulted in deletion of the IGF-I gene in the liver. Southern blot analysis revealed that the IGF-I gene-deletion effect was approximately 95% in the liver and undetectable in other tissues. Furthermore, IGF-I mRNA levels in liver, as determined by solution hybridization RNAse protection assays, were less than 1% of the levels in wild-type animals. In contrast, IGF-I mRNA levels measured in nonhepatic tissues such as heart, muscle, fat, spleen, and kidney were similar to control animals despite the increase in circulating GH (206). This lack of increase in nonhepatic tissue IGF-I mRNA is possibly due to these tissues being already maximally stimulated by factors other than GH, or that the lack of cyclical GH secretion affects the responsiveness of these tissues.
The effect of liver-specific IGF-I gene deletion on growth and
development was then tested. Circulating IGF-I levels in these animals
were markedly reduced at 6 weeks of age (only 25% of that in wild-type
animals). This was associated with an approximately 4-fold increase in
circulating GH levels, presumably due to the decrease in negative
feedback control by circulating IGF-I on GH secretion by the pituitary.
Measuring body weight twice weekly from ages 3 to 6 weeks assessed
postnatal growth and development (Fig. 6
). At age 6 weeks, mice were killed and
body length (nose to anus) was measured, femoral length was measured by
x-ray, and the weights of individual organs were recorded. None of
these measurements were significantly different between liver-specific
IGF-I knockout animals and their wild-type littermates. The only
exception was that the spleen showed a reduced size in the knockout
animals. The splenic size may be a result of chronically reduced levels
of circulating IGF-I. Sexual maturation was normal, as demonstrated by
normal fertility, normal size litters, and normal lactation and
weaning. Essentially, there were no phenotypic distinctions between the
liver-specific IGF-I gene-deleted animals and their wild-type
littermates. In a second model, we produced a liver-specific deletion
of the IGF-I gene by using an inducible interferon promoter to drive
the expression of cre. While the expression of cre is not liver
specific, in this model the deletion of the IGF-I gene was largely
specific to the liver and spleen. Once again, the circulating levels of
IGF-I were reduced by about 75%; however, postnatal growth and
development was considered normal (207).
|
At this stage it is still unclear whether the normal growth and development in these mice are due entirely to local IGF-I production or whether the free circulating IGF-I levels are sufficient to maintain this function. Preliminary studies suggest that circulating free IGF-I levels are normal and that the reduction in total IGF-I is due to the marked reduction in circulating IGFBP-3 levels (S. Yakar, J.-L. Liu, Y. Wu, J. Frystyk, S. Chernausek, and D. Le Roith, manuscript submitted). This could explain why when IGF-I receptor mRNA levels were measured in various tissues they were not different from those in wild-type mice. Since lowered circulating IGF-I levels can result in up-regulation of IGF-I receptor gene expression (209, 210), the absence of such up-regulation is consistent with the notion of local IGF-I production and action. Alternatively, free IGF-I levels are sufficient to maintain endocrine IGF-I-induced growth. However, it is clear that no compensation is seen with IGF-II since IGF-II mRNA levels in tissue and IGF-II protein levels in serum were both undetectable in the IGF-I gene-deleted mice.
| VII. Conclusion and Future Directions |
|---|
|
|
|---|
|
B. What is the function of circulating IGF?
Much new knowledge has been gained in the previous decade
concerning the function of the IGF system. We know now that it is an
exceedingly complex system, in large part due to the essentially
ubiquitous role played in controlling growth processes at the cellular
level. We also know that the regulation of the IGF system is not
limited to systemic GH. A major question that still remains to be
answered, however, is why the liver produces an output sufficient to
maintain such high levels of IGF-I (and IGF-II) in the circulation.
Mice lacking hepatic IGF-I have apparently normal growth. Furthermore,
a recent report has also shown that targeted deletion of the ALS gene,
which also results in a large (60%) reduction in circulating IGF-I
levels, is associated with only minor effects on growth rate and no
discernable effects on glucose metabolism (211). Thus the maintenance
of normal levels of IGF-I in the circulation is apparently not required
for normal growth. Does circulating IGF therefore represent a pool with
little bioactivity and destined only for clearance? What about free
IGF-I?
We would suggest that a possible reason for maintaining such high levels of circulating IGF-I is to keep GH secretion in check. In both models of conditional deletion of the hepatic igf-I gene, circulating GH levels are elevated (206, 207). Granted that the studies published to date have been on young (6- to 8-wk-old) animals or have only reported relatively short-term effects of the deficit. We might need to look at older (5- to 6-month-old) animals to see lesions associated with long-term excess GH secretion (e.g., glomerular hypertrophy, hyperinsulinemia and NIDDM, hypertriglyceridemia, hypertension, cardiomyopathies, increased occurrence of neoplastic diseases). At the time of writing, it has been shown that hyperinsulinemia is observed in liver igf-I null mice. Thus, we might be on the right track in reasoning that, rather than acting to promote growth, circulating IGF-I might actually serve to restrain the somatotropic axis. Only further studies will prove/disprove this hypothesis.
| Footnotes |
|---|
| References |
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signaling. J Biol Chem 271:2941529421
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growth factor II overexpression. J Biol Chem 274:1311813126
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M. Adriani, C. Garbi, G. Amodio, I. Russo, M. Giovannini, S. Amorosi, E. Matrecano, E. Cosentini, F. Candotti, and C. Pignata Functional Interaction of Common {gamma}-Chain and Growth Hormone Receptor Signaling Apparatus J. Immunol., November 15, 2006; 177(10): 6889 - 6895. [Abstract] [Full Text] [PDF] |
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T Ueland, S L Fougner, K Godang, T Schreiner, and J Bollerslev Serum GH and IGF-I are significant determinants of bone turnover but not bone mineral density in active acromegaly: a prospective study of more than 70 consecutive patients. Eur. J. Endocrinol., November 1, 2006; 155(5): 709 - 715. [Abstract] [Full Text] [PDF] |
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N. Abe, T. Matsunaga, K. Kameda, H. Tomita, T. Fujiwara, H. Ishizaka, H. Hanada, K. Fukui, I. Fukuda, T. Osanai, et al. Increased Level of Pericardial Insulin-Like Growth Factor-1 in Patients With Left Ventricular Dysfunction and Advanced Heart Failure J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1387 - 1395. [Abstract] [Full Text] [PDF] |
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Y. Wang, S. Nishida, T. Sakata, H. Z. Elalieh, W. Chang, B. P. Halloran, S. B. Doty, and D. D. Bikle Insulin-Like Growth Factor-I Is Essential for Embryonic Bone Development Endocrinology, October 1, 2006; 147(10): 4753 - 4761. [Abstract] [Full Text] [PDF] |
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K. Wagner, K. Hemminki, E. Grzybowska, R. Klaes, B. Burwinkel, P. Bugert, R. K. Schmutzler, B. Wappenschmidt, D. Butkiewicz, J. Pamula, et al. Polymorphisms in genes involved in GH1 release and their association with breast cancer risk Carcinogenesis, September 1, 2006; 27(9): 1867 - 1875. [Abstract] [Full Text] [PDF] |
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J.-C. Gabillard, K. Yao, M. Vandeputte, J. Gutierrez, and P.-Y. Le Bail Differential expression of two GH receptor mRNAs following temperature change in rainbow trout (Oncorhynchus mykiss). J. Endocrinol., July 1, 2006; 190(1): 29 - 37. [Abstract] [Full Text] [PDF] |
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P. J. Schlueter, T. Royer, M. H. Farah, B. Laser, S. J. Chan, D. F. Steiner, and C. Duan Gene duplication and functional divergence of the zebrafish insulin-like growth factor 1 receptors FASEB J, June 1, 2006; 20(8): 1230 - 1232. [Abstract] [Full Text] [PDF] |
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A. Sotiropoulos, M. Ohanna, C. Kedzia, R. K. Menon, J. J. Kopchick, P. A. Kelly, and M. Pende Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation PNAS, May 9, 2006; 103(19): 7315 - 7320. [Abstract] [Full Text] [PDF] |
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S. Yakar, M. L Bouxsein, E. Canalis, H. Sun, V. Glatt, C. Gundberg, P. Cohen, D. Hwang, Y. Boisclair, D. LeRoith, et al. The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone. J. Endocrinol., May 1, 2006; 189(2): 289 - 299. [Abstract] [Full Text] [PDF] |
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G. S. Mahmoud and L. M. Grover Growth Hormone Enhances Excitatory Synaptic Transmission in Area CA1 of Rat Hippocampus J Neurophysiol, May 1, 2006; 95(5): 2962 - 2974. [Abstract] [Full Text] [PDF] |
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J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [Abstract] [Full Text] [PDF] |
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R. M. Akers Major advances associated with hormone and growth factor regulation of mammary growth and lactation in dairy cows. J Dairy Sci, April 1, 2006; 89(4): 1222 - 1234. [Abstract] [Full Text] [PDF] |
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D. J. Chia, E. Subbian, T. M. Buck, V. Hwa, R. G. Rosenfeld, W. R. Skach, U. Shinde, and P. Rotwein Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction J. Biol. Chem., March 10, 2006; 281(10): 6552 - 6558. [Abstract] [Full Text] [PDF] |
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D. J. Chia, M. Ono, J. Woelfle, M. Schlesinger-Massart, H. Jiang, and P. Rotwein Characterization of Distinct Stat5b Binding Sites That Mediate Growth Hormone-stimulated IGF-I Gene Transcription J. Biol. Chem., February 10, 2006; 281(6): 3190 - 3197. [Abstract] [Full Text] [PDF] |
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R. P. Radcliff, B. L. McCormack, D. H. Keisler, B. A. Crooker, and M. C. Lucy Partial Feed Restriction Decreases Growth Hormone Receptor 1A mRNA Expression in Postpartum Dairy Cows J Dairy Sci, February 1, 2006; 89(2): 611 - 619. [Abstract] [Full Text] [PDF] |
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E. Menu, H. Jernberg-Wiklund, T. Stromberg, H. De Raeve, L. Girnita, O. Larsson, M. Axelson, K. Asosingh, K. Nilsson, B. Van Camp, et al. Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model Blood, January 15, 2006; 107(2): 655 - 660. [Abstract] [Full Text] [PDF] |
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M. Shimizu, B. R Beckman, A. Hara, and W. W Dickhoff Measurement of circulating salmon IGF binding protein-1: assay development, response to feeding ration and temperature, and relation to growth parameters J. Endocrinol., January 1, 2006; 188(1): 101 - 110. [Abstract] [Full Text] [PDF] |
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P. Haluska, J. M. Carboni, D. A. Loegering, F. Y. Lee, M. Wittman, M. G. Saulnier, D. B. Frennesson, K. R. Kalli, C. A. Conover, R. M. Attar, et al. In vitro and In vivo Antitumor Effects of the Dual Insulin-Like Growth Factor-I/Insulin Receptor Inhibitor, BMS-554417 Cancer Res., January 1, 2006; 66(1): 362 - 371. [Abstract] [Full Text] [PDF] |
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J Ayuk and M C Sheppard Growth hormone and its disorders Postgrad. Med. J., January 1, 2006; 82(963): 24 - 30. [Abstract] [Full Text] [PDF] |
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P J Jenkins, S Khalaf, W Ogunkolade, K McCarthy, T David, R E Hands, D Davies, and S A Bustin Differential expression of IGF-binding protein-3 in normal and malignant colon and its influence on apoptosis Endocr. Relat. Cancer, December 1, 2005; 12(4): 891 - 901. [Abstract] [Full Text] [PDF] |
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K Wagner, K Hemminki, E Israelsson, E Grzybowska, R Klaes, B Chen, D Butkiewicz, J Pamula, W Pekala, and A Forsti Association of polymorphisms and haplotypes in the human growth hormone 1 (GH1) gene with breast cancer Endocr. Relat. Cancer, December 1, 2005; 12(4): 917 - 928. [Abstract] [Full Text] [PDF] |
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M. Granado, T. Priego, A. I. Martin, M{a} A. Villanua, and A. Lopez-Calderon Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1007 - E1014. [Abstract] [Full Text] [PDF] |
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D. Fintini, M. Alba, and R. Salvatori Influence of Estrogen Administration on the Growth Response to Growth Hormone (GH) in GH-Deficient Mice Exp Biol Med, November 1, 2005; 230(10): 715 - 720. [Abstract] [Full Text] [PDF] |
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L. Huo, G. Fu, X. Wang, W. K. W. Ko, and A. O. L. Wong Modulation of Calmodulin Gene Expression as a Novel Mechanism for Growth Hormone Feedback Control by Insulin-like Growth Factor in Grass Carp Pituitary Cells Endocrinology, September 1, 2005; 146(9): 3821 - 3835. [Abstract] [Full Text] [PDF] |
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S. Fruchtman, J. G. Simmons, C. Z. Michaylira, M. E. Miller, C. J. Greenhalgh, D. M. Ney, and P. K. Lund Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells Am J Physiol Gastrointest Liver Physiol, August 1, 2005; 289(2): G342 - G350. [Abstract] [Full Text] [PDF] |
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J. Gibney, T. Wolthers, G. Johannsson, A. M. Umpleby, and K. K. Y. Ho Growth hormone and testosterone interact positively to enhance protein and energy metabolism in hypopituitary men Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E266 - E271. [Abstract] [Full Text] [PDF] |
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Z. Tang, R. Yu, Y. Lu, A. F. Parlow, and J.-L. Liu Age-dependent onset of liver-specific IGF-I gene deficiency and its persistence in old age: implications for postnatal growth and insulin resistance in LID mice Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E288 - E295. [Abstract] [Full Text] [PDF] |
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M Fernandez, F Sanchez-Franco, N Palacios, I Sanchez, and L Cacicedo IGF-I and vasoactive intestinal peptide (VIP) regulate cAMP-response element-binding protein (CREB)-dependent transcription via the mitogen-activated protein kinase (MAPK) pathway in pituitary cells: requirement of Rap1 J. Mol. Endocrinol., June 1, 2005; 34(3): 699 - 712. [Abstract] [Full Text] [PDF] |
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H.-j. Li, C.-y. Ji, W. Wang, and Y.-h. Hu A Twin Study for Serum Leptin, Soluble Leptin Receptor, and Free Insulin-Like Growth Factor-I in Pubertal Females J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3659 - 3664. [Abstract] [Full Text] [PDF] |
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Y. Guo, Y. Lu, D. Houle, K. Robertson, Z. Tang, J. J. Kopchick, Y. L. Liu, and J.-L. Liu Pancreatic Islet-Specific Expression of an Insulin-Like Growth Factor-I Transgene Compensates Islet Cell Growth in Growth Hormone Receptor Gene-Deficient Mice Endocrinology, June 1, 2005; 146(6): 2602 - 2609. [Abstract] [Full Text] [PDF] |
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J. D. Veldhuis, J. Frystyk, A. Iranmanesh, and H. Orskov Testosterone and Estradiol Regulate Free Insulin-Like Growth Factor I (IGF-I), IGF Binding Protein 1 (IGFBP-1), and Dimeric IGF-I/IGFBP-1 Concentrations J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2941 - 2947. [Abstract] [Full Text] [PDF] |
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P. E. Mullis, I. C. A. F. Robinson, S. Salemi, A. Eble, A. Besson, J.-M. Vuissoz, J. Deladoey, D. Simon, P. Czernichow, and G. Binder Isolated Autosomal Dominant Growth Hormone Deficiency: An Evolving Pituitary Deficit? A Multicenter Follow-Up Study J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2089 - 2096. [Abstract] [Full Text] [PDF] |
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H. Kim, E. Barton, N. Muja, S. Yakar, P. Pennisi, and D. LeRoith Intact Insulin and Insulin-Like Growth Factor-I Receptor Signaling Is Required for Growth Hormone Effects on Skeletal Muscle Growth and Function in Vivo Endocrinology, April 1, 2005; 146(4): 1772 - 1779. [Abstract] [Full Text] [PDF] |
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J Cruickshank, D I Grossman, R K Peng, T R Famula, and A M Oberbauer Spatial distribution of growth hormone receptor, insulin-like growth factor-I receptor and apoptotic chondrocytes during growth plate development J. Endocrinol., March 1, 2005; 184(3): 543 - 553. [Abstract] [Full Text] [PDF] |
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M. A Martin, P. Serradas, S. Ramos, E. Fernandez, L. Goya, M. N. Gangnerau, M. Lacorne, A. M. Pascual-Leone, F. Escriva, B. Portha, et al. Protein-Caloric Food Restriction Affects Insulin-Like Growth Factor System in Fetal Wistar Rat Endocrinology, March 1, 2005; 146(3): 1364 - 1371. [Abstract] [Full Text] [PDF] |
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Z. D. Sharp and A. Bartke Evidence for Down-Regulation of Phosphoinositide 3-Kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR)-Dependent Translation Regulatory Signaling Pathways in Ames Dwarf Mice J Gerontol A Biol Sci Med Sci, March 1, 2005; 60(3): 293 - 300. [Abstract] [Full Text] [PDF] |
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V. Cingel-Ristic, B. F. Schrijvers, A. K. van Vliet, R. Rasch, V. K. M. Han, S. L. S. Drop, and A. Flyvbjerg Kidney Growth in Normal and Diabetic Mice Is Not Affected by Human Insulin-Like Growth Factor Binding Protein-1 Administration Exp Biol Med, February 1, 2005; 230(2): 135 - 143. [Abstract] [Full Text] [PDF] |
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E. G. Brown, M. J. VandeHaar, K. M. Daniels, J. S. Liesman, L. T. Chapin, D. H. Keisler, and M. S. W. Nielsen Effect of Increasing Energy and Protein Intake on Body Growth and Carcass Composition of Heifer Calves J Dairy Sci, February 1, 2005; 88(2): 585 - 594. [Abstract] [Full Text] [PDF] |
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S. B. Roberts, L. A. R. McCauley, R. H. Devlin, and F. W. Goetz Transgenic salmon overexpressing growth hormone exhibit decreased myostatin transcript and protein expression J. Exp. Biol., October 1, 2004; 207(21): 3741 - 3748. [Abstract] [Full Text] [PDF] |
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V. Cingel-Ristic, J. W. van Neck, J. Frystyk, S. L. S. Drop, and A. Flyvbjerg Administration of Human Insulin-Like Growth Factor-Binding Protein-1 Increases Circulating Levels of Growth Hormone in Mice Endocrinology, September 1, 2004; 145(9): 4401 - 4407. [Abstract] [Full Text] [PDF] |
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J.-L. Liu, K. T. Coschigano, K. Robertson, M. Lipsett, Y. Guo, J. J. Kopchick, U. Kumar, and Y. L. Liu Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E405 - E413. [Abstract] [Full Text] [PDF] |
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P. Stattin, S. Rinaldi, C. Biessy, U.-H. Stenman, G. Hallmans, and R. Kaaks High Levels of Circulating Insulin-Like Growth Factor-I Increase Prostate Cancer Risk: A Prospective Study in a Population-Based Nonscreened Cohort J. Clin. Oncol., August 1, 2004; 22(15): 3104 - 3112. [Abstract] [Full Text] [PDF] |
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A. Baez-Saldana and E. Ortega Biotin Deficiency Blocks Thymocyte Maturation, Accelerates Thymus Involution, and Decreases Nose-Rump Length in Mice J. Nutr., August 1, 2004; 134(8): 1970 - 1977. [Abstract] [Full Text] [PDF] |
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T. Shavlakadze, M. Davies, J. D. White, and M. D. Grounds Early Regeneration of Whole Skeletal Muscle Grafts Is Unaffected by Overexpression of IGF-1 in MLC/mIGF-1 Transgenic Mice J. Histochem. Cytochem., July 1, 2004; 52(7): 873 - 883. [Abstract] [Full Text] [PDF] |
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J. M. Fitts, R. M. Klein, and C. A. Powers Comparison of Tamoxifen and Testosterone Propionate in Male Rats: Differential Prevention of Orchidectomy Effects on Sex Organs, Bone Mass, Growth, and the Growth Hormone-IGF-I Axis J Androl, July 1, 2004; 25(4): 523 - 534. [Abstract] [Full Text] [PDF] |
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R. G. Richards, D. M. Klotz, M. P. Walker, and R. P. DiAugustine Mammary Gland Branching Morphogenesis Is Diminished in Mice with a Deficiency of Insulin-like Growth Factor-I (IGF-I), But Not in Mice with a Liver-Specific Deletion of IGF-I Endocrinology, July 1, 2004; 145(7): 3106 - 3110. [Abstract] [Full Text] [PDF] |
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M. Koutsilieris, C. S. Mitsiades, J. Bogdanos, T. Dimopoulos, D. Karamanolakis, C. Milathianakis, and A. Tsintavis Combination of Somatostatin Analog, Dexamethasone, and Standard Androgen Ablation Therapy in Stage D3 Prostate Cancer Patients with Bone Metastases Clin. Cancer Res., July 1, 2004; 10(13): 4398 - 4405. [Abstract] [Full Text] [PDF] |
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S. I. Chisalita and H. J. Arnqvist Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E896 - E901. [Abstract] [Full Text] [PDF] |
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R. P. Rhoads, J. W. Kim, B. J. Leury, L. H. Baumgard, N. Segoale, S. J. Frank, D. E. Bauman, and Y. R. Boisclair Insulin Increases the Abundance of the Growth Hormone Receptor in Liver and Adipose Tissue of Periparturient Dairy Cows J. Nutr., May 1, 2004; 134(5): 1020 - 1027. [Abstract] [Full Text] [PDF] |
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J. Ayuk, R. N. Clayton, G. Holder, M. C. Sheppard, P. M. Stewart, and A. S. Bates Growth Hormone and Pituitary Radiotherapy, But Not Serum Insulin-Like Growth Factor-I Concentrations, Predict Excess Mortality in Patients with Acromegaly J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1613 - 1617. [Abstract] [Full Text] [PDF] |
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R. R. Kraemer, R. J. Durand, E. O. Acevedo, L. G. Johnson, G. R. Kraemer, E. P. Hebert, and V. D. Castracane Rigorous Running Increases Growth Hormone and Insulin-Like Growth Factor-I Without Altering Ghrelin Exp Biol Med, March 1, 2004; 229(3): 240 - 246. [Abstract] [Full Text] [PDF] |
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F. Tronche, C. Opherk, R. Moriggl, C. Kellendonk, A. Reimann, L. Schwake, H. M. Reichardt, K. Stangl, D. Gau, A. Hoeflich, et al. Glucocorticoid receptor function in hepatocytes is essential to promote postnatal body growth Genes & Dev., March 1, 2004; 18(5): 492 - 497. [Abstract] [Full Text] [PDF] |
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J. Woelfle and P. Rotwein In vivo regulation of growth hormone-stimulated gene transcription by STAT5b Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E393 - E401. [Abstract] [Full Text] [PDF] |
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H. M. Domene, S. V. Bengolea, A. S. Martinez, M. G. Ropelato, P. Pennisi, P. Scaglia, J. J. Heinrich, and H. G. Jasper Deficiency of the Circulating Insulin-like Growth Factor System Associated with Inactivation of the Acid-Labile Subunit Gene N. Engl. J. Med., February 5, 2004; 350(6): 570 - 577. [Full Text] [PDF] |
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A. Colao, D. Ferone, P. Marzullo, and G. Lombardi Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management Endocr. Rev., February 1, 2004; 25(1): 102 - 152. [Abstract] [Full Text] [PDF] |
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