INHIBITION OF STAT1-MEDIATED GENE ACTIVATION BY PIAS1

STAT (signal transducer and activator of transcription) proteins are l atent cytoplasmic transcription factors that become activated by tyros ine phosphorylation in response to cytokine stimulation. Tyrosine phos phorylated STATs dimerize and translocate into the nucleus to activate specific genes. Different members of the STAT protein family have dis tinct functions in cytokine signaling. Biochemical and genetic analysi s has demonstrated that Stat1 is essential for gene activation in resp onse to interferon stimulation. Although progress has been made toward understanding STAT activation, little is known about how STAT signals are down-regulated. We report here the isolation of a family of PIAS (protein inhibitor of activated STAT) proteins. PIAS1, but not other P IAS proteins, blocked the DNA binding activity of Stat1 and inhibited Stat1-mediated gene activation in response to interferon. Coimmunoprec ipitation analysis showed that PIAS1 was associated with Stat1 but not Stat2 or Stat3 after ligand stimulation. The in vivo PIAS1-Stat1 inte raction requires phosphorylation of Stat1 on Tyr-701. These results id entify PIAS1 as a specific inhibitor of Stat1-mediated gene activation and suggest that there may exist a specific BIAS inhibitor in every S TAT signaling pathway.