Angiotensin II Stimulates Sis-inducing Factor-like DNA Binding Activity. Evidence That the AT1A Receptor Activates Transcription Factor-Stat91 And/or a Related Protein

Recent studies on cytokine and growth factor stimulated signal transduction have defined a direct pathway (Stat91) linking cell surface receptors to target genes in the nucleus. The Stat91 pathway regulated c-fos 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 members of the STAT family of transcription factors. We determined whether angiotensin II (AII), which acts as a growth factor in many cell types, could activate the Stat91 pathway. We used neonatal rat cardiac fibroblasts expressing G-protein linked AII receptors and CHO-K1 cells expressing stably transfected angiotensin type 1A (AT1A) receptors to address this question. Angiotensin II induced SIF-like activity in both cell types, with initial induction at 15-30 min, maximal around 2-3 h, and undetectable at 6 h. Cytoplasmic and nuclear fractions from cells exposed to AII contained DNA binding activity to SIE. The SIF activity was insensitive to protein synthesis inhibitors and sensitive to the tyrosine kinase inhibitor genistein. Stat91 or a related protein was identified as a component of the AII-induced SIF complex and increased levels of this tyrosine-phosphorylated protein were found in nuclear extracts of cells treated with AII. This is the first evidence that a seven transmembrane, G-protein-coupled receptor, namely AT1A, activates the Stat91-nuclear signaling pathway.