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Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
Molecular Genetics and Metabolism (Impact Factor: 2.63). 03/2007; 90(2):126-33. DOI: 10.1016/j.ymgme.2006.10.006
Source: PubMed


Diverse physiological actions of growth hormone (GH) are mediated by changes in gene transcription. Transcription can be regulated at several levels, including post-translational modification of transcription factors, and formation of multiprotein complexes involving transcription factors, co-regulators and additional nuclear proteins; these serve as targets for regulation by hormones and signaling pathways. Evidence that GH regulates transcription at multiple levels is exemplified by analysis of the proto-oncogene c-fos. Among the GH-regulated transcription factors on c-fos, C/EBPbeta appears to be key, since depletion of C/EBPbeta by RNA interference blocks the stimulation of c-fos by GH. The phosphorylation state of C/EBPbeta and its ability to activate transcription are regulated by GH through MAPK and PI3K/Akt-mediated signaling cascades. The acetylation of C/EBPbeta also contributes to its ability to activate c-fos transcription. These and other post-translational modifications of C/EBPbeta appear to be integrated for regulation of transcription by GH. The formation of nuclear proteins into complexes associated with DNA-bound transcription factors is also regulated by GH. Both C/EBPbeta and the co-activator p300 are recruited to c-fos in response to GH, altering c-fos promoter activation. In addition, GH rapidly induces spatio-temporal re-localization of C/EBPbeta within the nucleus. Thus, GH-regulated gene transcription mediated by C/EBPbeta reflects the integration of diverse mechanisms including post-translational modifications, modulation of protein complexes associated with DNA and re-localization of gene regulatory proteins. Similar integration involving other transcription factors, including Stats, appears to be a feature of regulation by GH of other gene targets.

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Available from: Jorge Iniguez-Lluhi, Oct 03, 2015
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    • "Global expression analysis of GH actions in liver using microarrays clearly indicates that most of the known physiological effects of GH can be explained through its effects on the transcription of specific genes (Flores-Morales et al., 2001; Tollet-Egnell et al., 2001; Waxman and O’Connor, 2006; Ceseña et al., 2007; Vidal et al., 2007). To this end, GH is known to regulate a network of transcription factors that include, among others, nuclear receptors/transcription factors such as HNF (4α, 6, 3β), PPARα, CAR, FXR, SHP, SREBP, CRBP, C/EBPβ, and STAT5b. "
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    ABSTRACT: The liver responds to estrogens and growth hormone (GH) which are critical regulators of body growth, gender-related hepatic functions, and intermediate metabolism. The effects of estrogens on liver can be direct, through the direct actions of hepatic ER, or indirect, which include the crosstalk with endocrine, metabolic, and sex-differentiated functions of GH. Most previous studies have been focused on the influence of estrogens on pituitary GH secretion, which has a great impact on hepatic transcriptional regulation. However, there is strong evidence that estrogens can influence the GH-regulated endocrine and metabolic functions in the human liver by acting at the level of GHR-STAT5 signaling pathway. This crosstalk is relevant because the widespread exposition of estrogen or estrogen-related compounds in human. Therefore, GH or estrogen signaling deficiency as well as the influence of estrogens on GH biology can cause a dramatic impact in liver physiology during mammalian development and in adulthood. In this review, we will summarize the current status of the influence of estrogen on GH actions in liver. A better understanding of estrogen-GH interplay in liver will lead to improved therapy of children with growth disorders and of adults with GH deficiency.
    Frontiers in Endocrinology 06/2013; 4:66. DOI:10.3389/fendo.2013.00066
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    • "RNA from various tissues was extracted and RT-PCR was used to analyze the transcription of GH, GHR, c-fos (Cesena et al. 2007) and igf1 (Wood et al. 2005), which represent the ligand, receptor and targets in the signaling, in different tissues as well as in a series of developmental stages of wildtype zebrafish (Fig. 2a, b). "
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    ABSTRACT: Growth hormone (GH) gene transfer can markedly increase growth in transgenic fish. In the present study we have developed a transcriptional assay to evaluate GH-signal activation (GHSA) in zebrafish embryos. By analyzing the transcription of c-fos and igf1, and the promoter activity of spi2.1, in zebrafish embryos injected with different constructs, we found that overexpression of either GH or growth hormone receptor (GHR) resulted in GHSA, while a synergetic overexpression of GH and GHR gave greater activation. Conversely, overexpression of a C-terminal truncated dominant-negative GHR (ΔC-GHR) efficiently blocked GHSA epistatic to GH overexpression, demonstrating the requirement for a full GHR homodimer in signaling. In view of the importance of signal-competent GHR dimerization by extracellular GH, we introduced into zebrafish embryos a constitutively activated GHR (CA-GHR) construct, which protein products constitutively dimerize the GHR productively by Jun-zippers to activate downstream signaling in vitro. Importantly, overexpression of CA-GHR led to markedly higher level of GHSA than the synergetic overexpression of GH and GHR. CA-GHR transgenic zebrafish were then studied in a growth trial. The transgenic zebrafish showed higher growth rate than the control fish, which was not achievable by GH transgenesis in these zebrafish. Our study demonstrates GH-independent growth by CA-GHR in vivo which bypasses normal IGF-1 feedback control of GH secretion. This provides a novel means of producing growth enhanced transgenic animals based on molecular protein design.
    Transgenic Research 06/2011; 20(3):557-67. DOI:10.1007/s11248-010-9439-9 · 2.32 Impact Factor
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    • "Interestingly, recent studies suggest that different sites of C/EBPb may be phosphorylated in a sequential and orderly fashion (Tang et al., 2005; Cesena et al., 2006; Kim et al., 2007). "
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    ABSTRACT: Loss of muscle mass is commonly seen in patients with critical illness and is associated with increased expression of multiple genes controlling protein breakdown. Transcription factors that are activated during muscle wasting include NF-kB and members of the FOXO and C/EBP transcription factor families. The activity of these transcription factors is regulated by multiple posttranslational modifications, including ubiquitination, phosphorylation, and acetylation, providing for a complex and integrated network of regulatory mechanisms in muscle wasting. Targeting posttranslational modifications of transcription factors may prove important in the prevention and treatment of the debilitating consequences of muscle wasting.
    Journal of Cellular Physiology 12/2007; 213(3):679-89. DOI:10.1002/jcp.21190 · 3.84 Impact Factor
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