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J. Biol. Chem., Vol. 278, Issue 51, 51261-51266, December 19, 2003
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Mechanisms of Growth Hormone (GH) Action
IDENTIFICATION OF CONSERVED Stat5 BINDING SITES THAT MEDIATE GH-INDUCED INSULIN-LIKE GROWTH FACTOR-I GENE ACTIVATION*
¶||**
From the
Molecular Medicine Division, Department of Medicine and ¶Division of Endocrinology, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon 97239-3098
Many of the actions of growth hormone (GH) on somatic growth and tissue maintenance are mediated by insulin-like growth factor-I (IGF-I), a secreted protein whose gene expression is rapidly and potently induced by GH by unknown mechanisms. Recent studies implicating Stat5a and Stat5b in the growth response to GH in mice and observations linking Stat5b to control of IGF-I gene transcription in rats have prompted the current investigations into the molecular determinants of a putative regulatory network extending from GH through Stat5b to IGF-I. Here we characterize as critical components of this hormone-activated transcriptional pathway two adjacent Stat5 binding sites in the second intron of the rat IGF-I gene located within a conserved region previously found to undergo acute and reversible changes in chromatin structure after in vivo GH treatment. As assessed by chromatin immunoprecipitation assays, GH rapidly induced binding of Stat5 to this DNA segment in the liver of GH-deficient rats, just prior to the onset of transcription from both major and minor IGF-I gene promoters. Biochemical reconstitution experiments showed that the two intronic Stat5 DNA elements were able to bind Stat5b in vitro after GH treatment could transmit GH- and Stat5b-dependent transcriptional responsiveness to the major IGF-I promoter and to a minimal neutral gene promoter and were required for full stimulation of reporter gene activity by GH. Taken together, these results identify an intronic enhancer as a key mediator of GH-induced IGF-I gene transcription working through Stat5b and provide new insight into the molecular architecture of this transcriptional pathway.
Received for publication, August 26, 2003 , and in revised form, October 6, 2003.
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a research fellowship from the European Society for Pediatric Endocrinology sponsored by Novo Nordisk and the Eli Lilly International Foundation.
|| Supported by a research fellowship from the Lawson Wilkins Pediatric Endocrinology Society sponsored by Eli Lilly.
** To whom correspondence should be addressed: Oregon Health & Science University, Molecular Medicine Division, 3181 S. W. Sam Jackson Park Rd., Mail code HRC3, Portland, OR 97239-3098. Tel.: 503-494-0536; Fax: 503-494-7368; E-mail: rotweinp{at}ohsu.edu.
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