Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300

Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300

Divisions of ^*Endocrinology and Metabolism, and ^¶Cellular and Molecular Medicine, ^§Department of Medicine, ^†Howard Hughes Medical Institute, and ^‡Whittier Institute, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651

Abstract

We report that interferon γ (IFN-γ) 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-γ. Cells lacking STAT1 fail to inhibit AP-1/ets activity, and overexpression of CBP both potentiates IFN-γ-dependent transcription and relieves AP-1/ets repression. Thus, CBP and p300 integrate both positive and negative effects of IFN-γ on gene expression by serving as essential coactivators of STAT1α, modulating gene-specific responses to simultaneous activation of two or more signal transduction pathways.

Footnotes

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Michael G. Rosenfeld
Abbreviations: IFN-γ, interferon γ; M-CSF, macrophage colony-stimulating factor; GAS, gamma activated site; hGH, human growth hormone; GST, glutathione S-transferase; TPA, 12-O-tetradecanoylphorbol 13-acetate.