NUCLEAR INTEGRATION OF JAK STAT AND RAS/AP-1 SIGNALING BY CBP AND P300/

We report that interferon gamma (IFN-gamma) inhibits transcription of the macrophage scavenger receptor gene by antagonizing the Ras-depende nt activities of AP-1 and cooperating ets domain transcription factors , apparently as a result of competition between AP-1/ets factors and a ctivated STAT1 for limiting amounts of CBP and p300. Consistent with t his model, STAT1 alpha interacts directly with CBP in cells, and micro injection of anti-CBP and anti-p300 antibodies blocks transcriptional responses to IFN-gamma, Cells lacking STAT1 fail to inhibit AP-1/ets a ctivity, and overexpression of CBP both potentiates IFN-gamma-dependen t transcription and relieves AP-1/ets repression, Thus, CBP and p300 i ntegrate both positive and negative effects of IFN-gamma on gene expre ssion by serving as essential coactivators of STAT1 alpha, modulating gene-specific responses to simultaneous activation of two or more sign al transduction pathways.