Tissue-Specific Regulation of Growth Hormone (GH) Receptor and Insulin-Like Growth Factor-I Gene Expression in the Pituitary and Liver of GH-Deficient ( lit/lit ) Mice and Transgenic Mice that Overexpress Bovine GH (bGH) or a bGH Antagonist

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Endocrinology (Impact Factor: 4.5). 05/2004; 145(4):1564-70. DOI: 10.1210/en.2003-1486
Source: PubMed


GH has diverse biological actions that are mediated by binding to a specific, high-affinity cell surface receptor (GHR). Expression of GHR is tissue specific and a requirement for cellular responsiveness to GH. IGF-I is produced in multiple tissues and regulated in part by GH through GHR. In this study, we evaluated GHR and IGF-I mRNA expression in pituitary gland and compared the levels with those derived from liver of bovine GH transgenic, GH antagonist transgenic, lit/lit mice, and their respective controls using real-time RT-PCR. In liver, both GHR and IGF-I mRNA expressions were regulated in parallel with GH action in all three animal models, and there was a strong correlation between GHR and IGF-I mRNA levels. In the pituitary gland, increased expression of IGF-I mRNA in the pituitary of bovine GH transgenic mice was observed, whereas IGF-I expression in GH antagonist transgenic or lit/lit mice was similar to that observed in control animals. There were no differences of GHR mRNA levels in pituitary gland of any groups we examined. There was also no correlation between GHR and IGF-I mRNA levels in any group in the pituitary gland. In conclusion, we found that hepatic GHR and IGF-I mRNA levels were strongly correlated with each other in chronic GH excess or deficient state, and that regulation and correlation between local GHR and IGF-I mRNA levels induced by GH is different between liver and pituitary gland.

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    • "To examine GH expression in the pituitary, we quantified the amount of Gh mRNA by real-time RT-PCR. Quantities were corrected for the amount of 18S ribosomal RNA (rRNA) amplified, as reported (Iida et al., 2004). The Gh mRNA/18S rRNA values were not significantly different among the three Epha4 genotypes in each sex or between sexes (Figure 1F). "
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    ABSTRACT: The growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis mediates postnatal body growth. The GH receptor has been regarded as the sole receptor that mediates the Janus kinase 2 (JAK2)/signal transducers and activators of the transcription 5B (STAT5B) signal toward IGF1 synthesis. Here, we report a signaling pathway that regulates postnatal body growth through EphA4, a member of the Eph family of receptor tyrosine kinases and a mediator of the cell-cell contact-mediated signaling. EphA4 forms a complex with the GH receptor, JAK2, and STAT5B and enhances Igf1 expression predominantly via the JAK2-dependent pathway, with some direct effect on STAT5B. Mice with a defective Epha4 gene have a gene dose-dependent short stature and low plasma IGF1 levels. Igf1 messenger RNA (mRNA) in the liver and many other tissues was also significantly reduced in Epha4-knockout mice, whereas pituitary Gh mRNA and plasma GH levels were not. These findings suggest that the local cell-cell contact-mediated ephrin/EphA4 signal is as important as the humoral GH signal in IGF1 synthesis and body size determination
    Cell Reports 09/2012; 2(3):652–665. DOI:10.1016/j.celrep.2012.08.021 · 8.36 Impact Factor
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    • "In addition, IGF-I mRNA levels were increased in the liver but not the muscle or brain of rainbow trout after GH injection (Gahr et al., 2008). Conversely, a study by Iida et al. (2004) on GH transgenic mice suggested that IGF-I mRNA levels in the pituitary do increase when exposed to chronically higher GH, and that IGF-I is regulated differently between the pituitary and liver. There appears to be induction of IGF-I in non-hepatic tissues of GH transgenic coho salmon in the present study (which measured all IGF-I forms in total) but the manner by which various IGF-I transcripts may be involved needs to be determined and compared among species and transgenic strains. "
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    ABSTRACT: Non-transgenic (wild-type) coho salmon (Oncorhynchus kisutch), growth hormone (GH) transgenic salmon (with highly elevated growth rates), and GH transgenic salmon pair fed a non-transgenic ration level (and thus growing at the non-transgenic rate) were examined for plasma hormone concentrations, and liver, muscle, hypothalamus, telencephalon, and pituitary mRNA levels. GH transgenic salmon exhibited increased plasma GH levels, and enhanced liver, muscle and hypothalamic GH mRNA levels. Insulin-like growth factor-I (IGF-I) in plasma, and growth hormone receptor (GHR) and IGF-I mRNA levels in liver and muscle, were higher in fully fed transgenic than non-transgenic fish. GHR mRNA levels in transgenic fish were unaffected by ration-restriction, whereas plasma GH was increased and plasma IGF-I and liver IGF-I mRNA were decreased to wild-type levels. These data reveal that strong nutritional modulation of IGF-I production remains even in the presence of constitutive ectopic GH expression in these transgenic fish. Liver GHR membrane protein levels were not different from controls, whereas, in muscle, GHR levels were elevated approximately 5-fold in transgenic fish. Paracrine stimulation of IGF-I by ectopic GH production in non-pituitary tissues is suggested by increased basal cartilage sulphation observed in the transgenic salmon. Levels of mRNA for growth hormone-releasing hormone (GHRH) and cholecystokinin (CCK) did not differ between groups. Despite its role in appetite stimulation, neuropeptide Y (NPY) mRNA was not found to be elevated in transgenic groups.
    General and Comparative Endocrinology 09/2008; 159(1):26-37. DOI:10.1016/j.ygcen.2008.07.011 · 2.47 Impact Factor
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    • "PEPCK-bGH transgenic mice used in this work exhibit lifelong elevated bGH levels with a consequent increase in body weight (Sotelo et al. 1995, 1998, Miquet et al. 2004). In accordance with the positive regulation that chronic GH increase exerts over its receptor (McGrane et al. 1990, Iida et al. 2004, González et al. 2007), hepatic levels of GH receptor are increased in transgenic mice overexpressing GH (Aguilar et al. Figure 4 Normal mice (N) and PEPCK-bGH transgenic (T) mice were injected i.p. with normal saline (non-stimulated (K)) or oGH (5 mg/kg) (GH-stimulated (C)) and after 7 . 5 min and the livers were excised. "
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    ABSTRACT: Chronically elevated levels of GH in GH-transgenic mice result in accelerated growth and increased adult body weight. We have previously described that the GH-induced JAK2/STAT5-signaling pathway is desensitized in the liver of transgenic mice overexpressing GH. However, these animals present increased circulating IGF-I levels, increased hepatic GHR expression, and liver organomegaly due to hypertrophy and hyperplasia, which frequently progress to hepatomas as the animals age, indicating that action of GH on the liver is not prevented. In the present study, we have evaluated other GH-signaling pathways that could be activated in the liver of GH-transgenic mice. Upon GH administration, normal mice showed an important increment in STAT3 phosphorylation level, but transgenic mice did not respond to acute GH stimulation. However, STAT3 was constitutively phosphorylated in transgenic mice, whereas its protein content was not increased. GH-transgenic mice showed overexpression of c-Src, accompanied by an elevation of its activity. Other signaling mediators including focal adhesion kinase, epidermal growth factor receptor, Erk, Akt, and mammalian target of rapamycin displayed elevated protein and basal phosphorylation levels in these animals. Thus, GH-overexpressing transgenic mice exhibit hepatic upregulation of signaling mediators related to cell proliferation, survival, and migration. The upregulation of these proteins may represent GH-signaling pathways that are constitutively activated in the presence of dramatically elevated GH levels throughout life. These molecular alterations could be implicated in the pathological alterations observed in the liver of GH-transgenic mice.
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