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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

Departments of Biochemistry and Molecular Biology (M.O., D.J.C., P.R.) and Pediatrics (D.J.C.), Oregon Health & Science University, Portland, Oregon 97239; Department of Molecular Medicine and Surgery (R.M.-M., A.F.-M.), Karolinska Institute, 17176 Stockholm, Sweden; and Departments of Medicine and Physiology and Biophysics (T.G.U.), University of Illinois College of Medicine and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Peter Rotwein, Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 Southwest Sam Jackson Road, Mail Code L224, Portland, Oregon 97239. E-mail: rotweinp{at}ohsu.edu.

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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