In vivo regulation of growth hormone-stimulated gene transcription by STAT5b

Joachim Woelfle, Peter Rotwein

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

The long-term effects of growth hormone (GH) are mediated through coordinated changes in gene expression that are the outcome of interactions between hormone-activated signal transduction pathways and specific feedback loops. Recent studies in mice have implicated the transcription factor STAT5b as part of the GH-regulated somatic growth pathway, because mice lacking this protein showed diminished growth rates. To assess the role of Stat5b in GH-stimulated gene expression, we have delivered modified versions of the protein to the liver of pituitary-deficient male rats by quantitative adenovirus-mediated gene transfer. In pilot studies in cell culture, both constitutive-active and dominant-negative STAT5b showed appropriate binding properties toward a specific DNA response element. After in vivo expression, neither protein prevented nuclear accumulation of STATs 1 and 3 in the liver. Dominant-negative STAT5b completely inhibited GH-stimulated transcription of genes encoding the growth-promoting proteins IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS), which comprise the major circulating IGF-I complex, and blocked expression of the GH inhibitors SOCS-1, SOCS-2, and CIS, but had little effect on induction of SOCS-3. Constitutive-active STAT5b stimulated robust transcription of IGF-I, ALS, and IGFBP-3 in the absence of hormone but did little to modify GH-mediated activation of SOCS family genes. An adenovirus encoding EGFP was without effect. These results, in addition to establishing STAT5b as one of the key agents of GH-stimulated gene transcription, demonstrate the feasibility of using in vivo gene transfer to target and dissect the functions of distinct components of complex hormone-activated signal transduction pathways.

Original languageEnglish (US)
Pages (from-to)E393-E401
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume286
Issue number3 49-3
DOIs
StatePublished - Mar 2004

Keywords

  • Insulin-like growth factor I
  • Signal transducers and activators of transcription
  • Suppressors of cytokine signaling

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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