Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and P300

Abstract

We report that interferon χ (IFN-χ) inhibits transcription of the macrophage scavenger receptor gene by antagonizing the Ras-dependent activities of AP-1 and cooperating ets domain transcription factors, apparently as a result of competition between AP-1/ets factors and activated STAT1 for limiting amounts of CBP and p300. Consistent with this model, STAT1α interacts directly with CBP in cells, and microinjection of anti-CBP and anti-p300 antibodies blocks transcriptional responses to IFN-χ. Cells lacking STAT1 fail to inhibit AP-1/ets activity, and overexpression of CBP both potentiates IFN-χ-dependent transcription and relieves AP-1/ets repression. Thus, CBP and p300 integrate both positive and negative effects of IFN-χ on gene expression by serving as essential coactivators of STAT1α, modulating gene-specific responses hi simultaneous activation of two or more signal transduction pathways.