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Molecular and Cellular Biology, July 2000, p. 4699-4707, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Peroxisome Proliferator-Activated Receptor gamma -Dependent Repression of the Inducible Nitric Oxide Synthase Gene

Mei Li, Gabriel Pascual, and Christopher K. Glass*

Department of Cellular and Molecular Medicine and Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093-06511

Received 28 September 1999/Returned for modification 17 November 1999/Accepted 10 April 2000

The peroxisome proliferator-activated receptor gamma  (PPARgamma ) is a member of the nuclear receptor superfamily that activates target gene transcription in a ligand-dependent manner. In addition, liganded PPARgamma can inhibit transcription of genes induced by gamma interferon (IFN-gamma ) and/or lipopolysaccharides (LPSs), including the inducible nitric oxide synthase (iNOS) gene. Inhibition of the iNOS promoter is achieved partially through antagonizing the activities of NF-kappa B, AP-1, and STAT1, which are known to mediate effects of LPS and IFN-gamma . Previous studies have suggested that transrepression of these factors by nuclear receptors involves competition for limiting amounts of the general coactivators CREB-binding protein (CBP) and p300. CBP and p300 are thought to be recruited to nuclear receptors through bridging factors that include SRC-1, although CBP also interacts directly with PPARgamma through its amino terminus. These observations have raised questions concerning the involvement of SRC-1-like factors in CBP recruitment and transrepression. We here provide evidence that PPARgamma 's ability to repress iNOS transcription requires the ligand-dependent charge clamp that mediates interactions with CBP and SRC-1. Single amino acid mutations in PPARgamma that abolished ligand-dependent interactions with SRC-1 and CBP not only resulted in complete loss of transactivation activity but also abolished transrepression. Conversely, a CBP deletion mutant containing the SRC-1 interaction domain but lacking the N-terminal PPARgamma interaction domain was inactive as a PPARgamma coactivator and failed to rescue transrepression. Together, these findings are consistent with a model in which transrepression by PPARgamma is achieved by targeting CBP through direct interaction with its N-terminal domain and via SRC-1-like bridge factors.

* Corresponding author. Mailing address: Department of Cellular and Molecular Medicine and Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0651. Phone: (858) 534-6011. Fax: (858) 822-2127. E-mail: cglass{at}ucsd.edu.

Molecular and Cellular Biology, July 2000, p. 4699-4707, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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