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Growth Hormone Stimulates Interferon Regulatory Factor-1 Gene Expression in the Liver¹

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Peter Rotwein, Molecular Medicine Division, Department of Medicine, Oregon Health Sciences University, 3181 Southwest Sam Jackson Park Road, NRC 514, Portland, Oregon 97201-3098. E-mail: rotweinp{at}ohsu.edu

Interferon regulatory factor-1 (IRF-1) is a transcription factor first identified as part of the nuclear response to interferons. IRF-1 has been shown to be activated by many cytokines, including PRL, and has been thought to play a role in PRL-regulated gene expression in several experimental systems, including the Nb2 T lymphoma cell line, where it was first characterized as a PRL-responsive gene. We now find that IRF-1 gene expression is rapidly activated in vivo by both PRL and GH treatment. A single ip injection of rat PRL to hypophysectomized female rats caused a transient increase in nascent hepatic nuclear IRF-1 RNA within 15 min of hormone treatment. The rise in IRF-1 transcripts was accompanied by induction of nuclear protein binding to a DNA element from the proximal IRF-1 promoter, as assessed by gel mobility shift assays; this element was shown previously to mediate PRL-activated gene transcription. GH treatment stimulated a greater and more sustained increase in nascent IRF-1 RNA than PRL, leading to accumulation of IRF-1 transcripts for up to 16 h after a single hormone injection. GH also caused a pronounced induction of hepatic nuclear protein binding to the IRF-1 promoter element. Supershift experiments with specific antibodies showed that signal transducer and activator of transcription 1 (STAT1) and to a lesser extent STAT3 were components of the GH-activated protein-DNA complexes. By contrast, these two STATs were not induced in the liver by PRL. Protein binding to the IRF-1 DNA element and IRF-1 gene activation by GH were not blunted by pretreatment with the protein synthesis inhibitor, cycloheximide, indicating that these hormonal effects are primary consequences of GH-activated signal transduction pathways. Our results identify another component of the rapid nuclear response to GH, and support the idea that multiple primary and secondary signaling pathways contribute to the acute actions of GH on gene expression.

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