ANGIOTENSIN-II STIMULATES SIS-INDUCING FACTOR-LIKE DNA-BINDING ACTIVITY - EVIDENCE THAT THE AT(1A) RECEPTOR ACTIVATES TRANSCRIPTION FACTOR-STAT91 AND OR A RELATED PROTEIN/

Recent studies on cytokine and growth factor stimulated signal transdu ction have defined a direct pathway (Stat91) linking cell surface rece ptors to target genes in the nucleus. The Stat91 pathway regulated c-f os gene transcription involves activation by tyrosine phosphorylation of the DNA binding factor SIF (sis-inducing factor) in the cytoplasm, its nuclear translocation, and interaction with the regulatory element SIE (sis-inducing element). SIF is a complex of proteins containing m embers of the STAT family of transcription factors. We determined whet her angiotensin II (ATI), which acts as a growth factor in many cell t ypes, could activate the Stat91 pathway. We used neonatal rat cardiac fibroblasts expressing G-protein linked AII receptors and CHO-gl cells expressing stably transfected angiotensin type 1A (AT,) receptors to address this question. Angiotensin II induced SIF-like activity in bot h cell types, with initial induction at 15-30 min, maximal around 2-3 h, and undetectable at 6 h. Cytoplasmic and nuclear fractions from cel ls exposed to AII contained DNA binding activity to SIE. The SIF activ ity was insensitive to protein synthesis inhibitors and sensitive to t he tyrosine kinase inhibitor genistein. Stat91 or a related protein wa s identified as a component of the AII-induced SIF complex and increas ed levels of this tyrosine phosphorylated protein were found in nuclea r extracts of cells treated with AII. This is the first evidence that a seven transmembrane, G-protein-coupled receptor, namely AT(1A), acti vates the Stat91-nuclear signaling pathway.