ACTIVATION OF ACUTE-PHASE RESPONSE FACTOR (APRF) STAT3 TRANSCRIPTION FACTOR BY GROWTH-HORMONE/

The mechanisms by which the binding of growth hormone (GH) to its cell surface receptor elicits changes in gene transcription are largely un known. The transcription factor Stat1/p91 has been shown to be activat ed by GH Here we show that acute phase response factor or Stat3 (or an antigenically related protein), is also activated by GH, Stats has be en implicated in the interleukin-6-dependent induction of acute phase response genes, GH promotes in 3T3-F442A fibroblasts the tyrosyl phosp horylation of a protein immunoprecipitated by antibodies to Stats. Thi s protein co-migrates with a tyrosyl phosphorylated protein from cells treated with leukemia inhibitory factor, a cytokine known 60 activate Stat3. Tyrosyl phosphorylated Stats is also observed in response to i nterferon-gamma. Stat3 is present in GH-inducible DNA-binding complexe s that bind the sis-inducible element in the c-fos promoter and the ac ute phase response element in the alpha(2),-macroglobulin promoter. Th e 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 transcriptio n factors among hormones and cytokines that activate JAK kinases provi de an explanation for shared responses, while the ability of the diffe rent Ligands to differentially recruit various Stat family members sug gests mechanisms by which specificity in gene regulation could be achi eved.