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Molecular and Cellular Biology, July 2000, p. 4699-4707, Vol. 20, No. 13
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
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Peroxisome Proliferator-Activated Receptor
-Dependent
Repression of the Inducible Nitric Oxide Synthase Gene
(PPAR
) is a
member of the nuclear receptor superfamily that activates target gene
transcription in a ligand-dependent manner. In addition, liganded
PPAR
can inhibit transcription of genes induced by gamma interferon (IFN-
) 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-
B, AP-1, and STAT1, which are known to mediate effects of LPS and IFN-
. 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 PPAR
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
PPAR
'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 PPAR
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
PPAR
interaction domain was inactive as a PPAR
coactivator and
failed to rescue transrepression. Together, these findings
are consistent with a model in which transrepression by PPAR
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.
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