Signal Transducer and Activator of Transcription (Stat) 5b-Mediated Inhibition of Insulin-Like Growth Factor Binding Protein-1 Gene Transcription: A Mechanism for Repression of Gene Expression by Growth Hormone

University of Illinois at Chicago, Chicago, Illinois, United States
Molecular Endocrinology (Impact Factor: 4.02). 06/2007; 21(6):1443-57. DOI: 10.1210/me.2006-0543
Source: PubMed


GH plays a central role in controlling somatic growth, tissue regeneration, and intermediary metabolism in most vertebrate species through mechanisms dependent on the regulation of gene expression. Recent studies using transcript profiling have identified large cohorts of genes whose expression is induced by GH. Other results have demonstrated that signal transducer and activator of transcription (Stat) 5b, a latent transcription factor activated by the GH receptor-associated protein kinase, Jak2, is a key agent in the GH-stimulated gene activation that leads to somatic growth. By contrast, little is known about the steps through which GH-initiated signaling pathways reduce gene expression. Here we show that Stat5b plays a critical role in the GH-regulated inhibition of IGF binding protein-1 gene transcription by impairing the actions of the FoxO1 transcription factor on the IGF binding protein-1 promoter. Additional observations using transcript profiling in the liver indicate that Stat5b may be a general mediator of GH-initiated gene repression. Our results provide a model for understanding how GH may simultaneously stimulate and inhibit the expression of different cohorts of genes via the same transcription factor, potentially explaining how GH action leads to integrated biological responses in the whole organism.

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Available from: Amilcar Flores-Morales, Oct 09, 2015
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    • "The effect of increased IGFBP-1 can be predicted to reduce further the free fraction of IGF-I, which would be expected to reduce its activity. Interestingly, the activation of GH-STAT5b signaling induces the expression of ALS and IGF-I but inhibits IGFBP-1 (Ono et al., 2007). Therefore, the inhibition of GHR-JAK2-STAT5 signaling pathway in liver (see below), most likely contributes to the effects of estrogens on IGF-I, ALS, and IGFBP-1. "
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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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    • "While the majority of FoxO1-related research focuses on the FoxO1 function as a transcriptional activator/repressor, the underlying mechanisms that govern FoxO1 gene transcription per se are largely unknown. It has been shown that members of the STAT family of transcription factors can bind FoxO1 promoter (Luo et al, 2011; Ono et al, 2007) and STAT1 exerts a negative role on FoxO1 promoter activity in RINm5F cells (Luo et al, 2011). "
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    ABSTRACT: ADAM17 and its inhibitor TIMP3 are involved in nephropathy, but their role in diabetic kidney disease (DKD) is unclear. Diabetic Timp3−/− mice showed increased albuminuria, increased membrane thickness and mesangial expansion. Microarray profiling uncovered a significant reduction of Foxo1 expression in diabetic Timp3−/− mice compared to WT, along with FoxO1 target genes involved in autophagy, while STAT1, a repressor of FoxO1 transcription, was increased. Re-expression of Timp3 in Timp3−/− mesangial cells rescued the expression of Foxo1 and its targets, and decreased STAT1 expression to control levels; abolishing STAT1 expression led to a rescue of FoxO1, evoking a role of STAT1 in linking Timp3 deficiency to FoxO1. Studies on kidney biopsies from patients with diabetic nephropathy confirmed a significant reduction in TIMP3, FoxO1 and FoxO1 target genes involved in autophagy compared to controls, while STAT1 expression was strongly increased. Our study suggests that loss of TIMP3 is a hallmark of DKD in human and mouse models and designates TIMP3 as a new possible therapeutic target for diabetic nephropathy.
    EMBO Molecular Medicine 03/2013; 5(3). DOI:10.1002/emmm.201201475 · 8.67 Impact Factor
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    ABSTRACT: Taurine is the most abundant free amino acid in the body and is present at high concentrations during development and in the early milk. It is synthesized from cysteine via oxidation of cysteine to cysteinesulfinate by the enzyme cysteine dioxygenase (CDO), followed by the decarboxylation of cysteinesulfinate to hypotaurine, catalyzed by cysteine sulfinic acid decarboxylase (CSAD). To determine whether the taurine biosynthetic pathway is present in mammary gland and whether it is differentially expressed during pregnancy and lactation, and also to further explore the possible regulation of hepatic taurine synthesis during pregnancy and lactation, we measured mammary and hepatic CDO and CSAD mRNA and protein concentrations and tissue, plasma and milk taurine concentrations. CDO and CSAD mRNA and protein were expressed in mammary gland and liver regardless of physiological state. Immunohistochemistry demonstrated the expression of CDO in ductal cells of pregnant rats, but not in other mammary epithelial cells or in ductal cells of nonpregnant rats. CDO was also present in stromal adipocytes in mammary glands of both pregnant and nonpregnant rats. Our findings support an upregulation of taurine synthetic capacity in the mammary gland of pregnant rats, based on mammary taurine and hypotaurine concentrations and the intense immunohistochemical staining for CDO in ductal cells of pregnant rats. Hepatic taurine synthetic capacity, particularly CSAD, and taurine concentrations were highest in rats during the early stages of lactation, suggesting the liver may also play a role in the synthesis of taurine to support lactation or repletion of maternal reserves.
    Journal of Nutrition 09/2007; 137(8):1887-94. · 3.88 Impact Factor
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