Mechanisms of growth hormone (GH) action

Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation

Joachim Woelfle, Dennis J. Chia, Peter Rotwein

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)51261-51266
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number51
DOIs
StatePublished - Dec 19 2003
Externally publishedYes

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Insulin-Like Growth Factor I
Transcriptional Activation
Growth Hormone
Genes
Chemical activation
Binding Sites
Transcription
Rats
Chromatin
Chromatin Immunoprecipitation
DNA
Growth
Reporter Genes
Gene expression
Liver
Introns
Assays
Maintenance
Hormones
Tissue

ASJC Scopus subject areas

  • Biochemistry

Cite this

Mechanisms of growth hormone (GH) action : Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation. / Woelfle, Joachim; Chia, Dennis J.; Rotwein, Peter.

In: Journal of Biological Chemistry, Vol. 278, No. 51, 19.12.2003, p. 51261-51266.

Research output: Contribution to journalArticle

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