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Submitted on December 18, 2006
Accepted on April 5, 2007
Departments of Biochemistry and Molecular Biology and Pediatrics, Oregon Health & Science University, Portland, Oregon, USA 97239; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Departments of Medicine and Physiology and Biophysics, University of Illinois College of Medicine and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
* To whom correspondence should be addressed. E-mail: rotweinp{at}ohsu.edu.
Growth hormone (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. Others results have demonstrated that Stat5b, 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 (IGFBP-1) gene transcription by impairing the actions of the FoxO1 transcription factor on the IGFBP-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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