GROWTH-HORMONE RAPIDLY ACTIVATES RAT SERINE-PROTEASE INHIBITOR-2.1 GENE-TRANSCRIPTION AND INDUCES A DNA-BINDING ACTIVITY DISTINCT FROM THOSE OF STAT1, STAT3, AND STAT4

Transcriptional regulation by growth hormone (GN) represents the culmi nation of signal transduction pathways that are initiated by the cell surface GH receptor and are targeted to the nucleus. Recent studies ha ve demonstrated that the activated GH receptor can stimulate Stat1, a cytoplasmic transcription factor that becomes tyrosine phosphorylated and translocates to the nucleus, where it can interact with specific D NA sequences to modulate gene expression. GH also has been found to in duce protein binding to a portion of the rat serine protease inhibitor (Spi) 2.1 gene promoter that is required for GH-induced transcription of Spi 2.1. Using GH deficient hypophysectomized rats as a model, we show that GH treatment rapidly and potently induces both nuclear Spi 2 .1 mRNA expression in the liver and specific nuclear protein binding t o a 45-bp segment of the Spi 2.1 gene promoter. A GH-inducible gel-shi fted complex appears within 15 min of systemic hormone administration and can be inhibited by an antiphosphotyrosine monoclonal antibody but is not blocked by a polyclonal antiserum to Stat1, Stat3, or Stat4, e ven though the nucleotide sequence contains two gamma interferon-activ ated sequence like elements that could interact with STAT proteins. By Southwestern (DNA-protein) blot analysis, similar to 41- and 35-kDa G H-inducible proteins were detected in hepatic nuclear extracts with th e Spi 2.1 DNA probe. Thus, a GH-activated signaling pathway stimulates Spi 2.1 gene expression through a unique mechanism that does not appe ar to involve known members of the STAT family of transcription factor s.