Abstract
The mechanism by which the binding of growth hormone (GH) to its cell surface receptor elicits changes in gene transcription are largely unknown. The transcription factor Stat1/p91 has been shown to be activated by GH. Here we show that acute phase response factor or Stat3 f1p4an antigenically related protein), is also activated by GH. Stat3 has been implicated in the interleukin-6-dependent induction of acute phase response genes. GH promotes in 3T3-F442A fibroblasts the tyrosyl phosphorylation of a protein immunoprecipitated by antibodies to Stat3. This protein co-migrates with a tyrosyl phosphorylated protein from cells treated with leukemia inhibitory factor, a cytokine known to activate Stat3. Tyrosyl phosphorylated Stat3 is also observed in response to interferon-gamma. Stat3 is present in GH-inducible DNA-binding complexes that bind the sis-inducible element in the c-fos promoter and the acute phase response element in the alpha 2-macroglobulin promoter. The ability of GH to activate both Stat1 and Stat3 (i.e. increase their tyrosyl phosphorylation and ability to bind to DNA) suggests that gene regulation by GH involves multiple Stat proteins. Shared transcription factors among hormones and cytokines that activate JAK kinases provide an explanation for shared responses, while the ability of the different ligands to differentially recruit various Stat family members suggests mechanisms by which specificity in gene regulation could be achieved.
Highlights
We show that acute phase response factor or 8tat3, is activated by growth hormone (GH). 8ta13 has been implicated in the interleukin-6-dependent induction of acute phase response genes
GH promotes in 3T3-F442A fibroblasts the tyrosyl phosphorylation of a protein immunoprecipitated by antibodies to 8tat3
Tyrosyl phosphorylated 8ta13 is observed in response to interferon-yo Stat3 is present in GH-inducible DNA-binding complexes that bind the sis-inducible element in the c-fos promoter and the acute phase response element in the 0i2-macroglobulin promoter
Summary
Vol 270, No., Issue of February 24, pp. 3974-3979, 1995 Printed in U.S.A. Activation of Acute Phase Response Factor (APRF)/Stat Transcription Factor by Growth Hormone*. Shared transcription factors among hormones and cytokines that activate JAK kinases provide an explanation for shared responses, while the ability of the different ligands to differentially recruit various Stat family members suggests mechanisms by which specificity in gene regulation could be achieved. StatIo ( referred to as Statl) has been identified as a component of DNA-binding complexes formed in response to multiple growth and differentiation factors which signal via JAK kinases (e.g. IFN-y, IL-6, LIF, oncostatin M) [8,9,10,11,12,13,14]. In IM-9 cells, a 93-kDa tyrosyl phosphorylated protein antigenically related to, but distinct from, Statl was present in GH-induced DNA-binding complexes capable of binding to a y response region from IFN-y induced genes [25].
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