MinireviewMultiple mechanisms of growth hormone-regulated gene transcription
Introduction
Pituitary growth hormone (GH) has long been known as a major regulator of normal growth and metabolism [1], [2], [3]. Among its diverse actions, GH promotes statural growth in conjunction with insulin-like growth factor 1 (IGF-1) by stimulating chondrocytes in long bones [4], [5], [6], [7]. GH promotes a relative increase in lean body mass and decrease in body lipid, reflecting changes that include the ability of GH to increase cellular protein synthesis, stimulate lipolysis and impair lipogenesis under physiological conditions [8], [9]. GH excess can result in acromegaly and insulin resistance [8], [10], [11].
GH-regulated gene transcription underlies many of the diverse responses to GH (Fig. 1). These responses are initiated by the interaction of GH with the GH receptor, a member of the cytokine receptor superfamily [12], [13]. Janus kinase 2 (JAK2), a non-receptor tyrosine kinase, associates with dimerized GH receptors [14]. The activated JAK2 phosphorylates itself and the cytoplasmic domain of the GH receptor to initiate downstream signaling. Cytoplasmic signaling molecules, including signal transducers and activators of transcription (Stats), pathways mediated by mitogen activated protein kinases (MAPKs), and phosphatidyl inositol 3′ kinase (PI3K), relay GH signals to the nuclei of target cells to modulate gene transcription [12], [13], [15], [16].
Changes in gene transcription in response to GH occur at multiple levels, including post-translational modifications of nuclear proteins, formation of nucleoprotein complexes and cellular re-localization of factors that regulate transcription. While some aspects of these events have been analyzed for the signal transducers and activators of transcription (Stats), this review focuses on regulation of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor essential for GH-stimulated c-fos expression and serves to illustrate the complexity in the diverse mechanisms of gene regulation by GH.
Section snippets
GH regulates transcription by modifying the activity of multiple transcription factors
As part of the mechanism of gene regulation by GH, it has been amply demonstrated that Stat family members, especially Stat 5a and 5b, mediate the GH-dependent activation of a number of genes [15]. Interaction of GH with its receptors activates the tyrosine kinase Jak2, which phosphorylates and activates cytoplasmic Stats 1, 3, and 5. Phosphorylated Stats translocate to the nucleus and bind to DNA elements within GH target genes [17]. Stat 5b has been implicated in the transcription of multiple
GH regulates transcription factors through a variety of post-translational modifications
The demonstration that GH activates Stats by stimulating their tyrosine phosphorylation was a landmark in understanding GH signaling [35], [36], [38]. The importance of other signaling events in GH-stimulated transcription is demonstrated by observations of GH-regulated changes in the phosphorylation state of C/EBPβ (Fig. 2A). Isoelectric focusing identified at least six different phosphorylated forms of C/EBPβ that are regulated by GH in 3T3-F442A cells [57]. A MAPK substrate site at T235 in
GH regulates the composition of nucleoprotein complexes that mediate gene transcription
Our current understanding of transcription supports a mechanism in which binding of regulated sequence-specific transcription factors, such as the GH-regulated Stats and C/EBPβ, to their cognate response elements, provides a platform for formation of multiprotein complexes. The complexes often include factors such as co-activators, co-repressors, HATS, HDACs, chromatin remodeling factors and other proteins, which communicate signals from regulated factors to the general transcription machinery
GH regulates the cellular localization of transcription factors
The cellular localization of gene regulatory proteins is an important determinant of transcription. It is well established that activation of Stats 1, 3, and 5 by GH is accompanied by their translocation from the cytoplasm to nucleus, where they activate target genes [15]. In the case of C/EBPβ, its subnuclear localization appears to be a regulated event [81]. Immunofluorescence analysis of the nuclear localization of C/EBPβ revealed that GH dramatically shifts the distribution of C/EBPβ within
GH regulates transcription by multiple mechanisms
GH regulates transcription by multiple mechanisms involving a variety of post-translational modifications of transcription factors, dynamic assembly of nucleoprotein complexes and re-localization of transcription regulatory proteins in target cells. These mechanisms apply not only to Stat-dependent effects of GH, but are also involved in the similarly complex C/EBPβ-dependent transcription of GH-stimulated target genes. The following model is suggested for C/EBPβ-mediated transcription of
Acknowledgments
These studies were supported by NIH Grant DK46072 and NSF Grant 00-80193 to J. Schwartz, by NIH Grant 5P60 DK20572 to R. Kwok, NIH Grant DK061656 to J. Iñiguez-Lluhí. This work used multiple core facilities of the Michigan Diabetes Research and Training Center funded by NIH (5P60DK20572). T. Cesena was supported by an individual NIH predoctoral fellowship (DK074377), a predoctoral traineeship from the Center for Organogenesis (NIH T32-HD07505), the Training Program in Cellular and Molecular
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Sex steroids and growth hormone interactions
2016, Endocrinologia y NutricionCitation Excerpt :Activated JAK2 phosphorylates the GHR cytoplasmic domain on tyrosine residues and subsequent JAK2-dependent and -independent intracellular signal transduction pathways evoke cell responses including changes in gene transcription, proliferation, cytoskeletal re-organization, and lipid and glucose metabolism. STAT5 phosphorylation by JAK2 results in their dissociation from the receptor, dimerization, and translocation to the nucleus, where they modulate the transcription of target genes such as IGF-I, SOCS2, CYP2C12 and HNF6.35–38 STAT5b is a key transcription factor in GH regulation of target genes associated with body growth, intermediate metabolism (e.g., lipid metabolism) and gender dimorphism, even though STAT1, 3, and 5a have also been shown to be recruited by the GHR.
Cellular and Molecular Mechanisms of Protein Synthesis Among Tissues
2016, The Molecular Nutrition of Amino Acids and Proteins: A Volume in the Molecular Nutrition SeriesReciprocal occupancy of BCL6 and STAT5 on Growth Hormone target genes: Contrasting transcriptional outcomes and promoter-specific roles of p300 and HDAC3
2014, Molecular and Cellular EndocrinologyCitation Excerpt :This suggests that reciprocal regulation of Socs2, Cish and Bcl6 by BCL6 and STAT5 in response to external stimuli may occur in multiple cells types, although the precise molecular mechanisms and co-regulatory molecules involved are likely to differ. Post-translational modifications to BCL6 (Bereshchenko et al., 2002; Moriyama et al., 1997; Niu et al., 1998) and STAT5 (Cesena et al., 2007b; Herrington et al., 2000) such as phosphorylation and acetylation induced by signaling molecules activated by GH could also influence the association of co-activators or co-repressors with BCL6 and STAT5 and the recruitment of these complexes to specific genes (Icardi et al., 2012; Mendez et al., 2008). Recent studies have shown that Rac1 signaling induces a BCL6/STAT5 transcriptional switch on cell-cycle-associated target gene promoters (Barros et al., 2012).
Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia
2013, Molecular Genetics and MetabolismCitation Excerpt :In contrast, hepatic expression of IGF 2 mRNA was normal (Fig. 1C). Moreover, hepatic levels of phosphorylated STAT5 (phospho Y694) and c-Fos were reduced in both glucose-treated and untreated G6pase (−/−) mice compared with G6pase (+/+) mice, consistent with decreased hepatic GH signaling [28] (Figs. 2A, B). Accordingly, the administration of GH and glucose caused little or no increase in hepatic IGF 1 mRNA in GT G6pase (−/−) mice compared with G6pase (+/+) mice (Fig. 2D), and GH-stimulated weight gain was blunted in comparison to that observed in wild-type mice: GH treatment for 7 days increased body weight by 38% (p < 0.02) in unaffected [G6pase (+/+) and (+/−)] controls but had no significant effect in G6pase (−/−) mice (Fig. 2C).
Phosphorylation of sterol regulatory element-binding protein (SREBP)-1a links growth hormone action to lipid metabolism in hepatocytes
2010, AtherosclerosisCitation Excerpt :We have previously shown that S117 is the main phosphorylation site in SREBP-1a of MAPK cascade [7,8]. On the other hand GH alters the phosphorylation status of C/EBPβ via PI3K/AKT/GSK-3 to attenuate transcription [17]. GSK-3 phosphorylates SREBP-1 at T426 and S430 and phosphorylation of these sites has also been shown to influence protein stability [18].
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These authors contributed equally to this work.
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Present address: Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA.