MODULATION OF INTERFERON ACTION BY RETINOIDS - INDUCTION OF MURINE STAT1 GENE-EXPRESSION BY RETINOIC ACID

We have previously demonstrated that up regulation of STAT1 protein by all-trans-retinoic acid (RA) in interferon (IFN)-unresponsive cells p ermits growth inhibition by IFNs. Here, we show that the promoter of S TAT1 directly responds to retinoic acid treatment, Sequence and functi onal analysis of the murine STAT1 promoter have identified a direct re peat motif that serves as a retinoic acid response: element, Mutagenes is of this element resulted in a loss of response to RA. This element is activated by RA receptors alpha, beta, and gamma. In vivo, RA recep tor beta and retinoid X receptor alpha preferentially interacted with this element. Thus, these data define a molecular basis for the synerg y between IFNs and retinoids in tumor growth inhibition.