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
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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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    • "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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