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Cited by 377Peroxisome Proliferator-Activated ReceptorsNuclear Receptors and SignalingCytokine Signaling Pathways and Interactions

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

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Li, Mei, Pascual, Gabriel, Glass, Christopher K.·2000·Molecular and Cellular Biology
DOI 10.1128/mcb.20.13.4699-4707.2000PMC PMC85890
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Abstract

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-kappaB, 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.

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  • In macrophages, PPARγ represses inducible nitric-oxide synthase induction and concomitant NO production.

    “In macrophages PPAR␥ represses inducible nitric-oxide (NO) synthase induction as well as concomitant NO production (11)”

    From MicroRNA-27b Contributes to Lipopolysaccharide-mediated Peroxisome Proliferator-activated Receptor γ (PPARγ) mRNA Destabilization (2010) · cites this paper as [11]

    The Abstract states that liganded PPARγ inhibits induction of the iNOS gene in monocytes/macrophages, and the Results report repression of LPS-induced iNOS promoter activity. The cited paper does not report a corresponding reduction in NO production, so that part of the claim is unsupported. (LLM, conf=0.86)

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Authors
Li, M., Pascual, G., & Glass, C. K.
Affiliations
University of California San Diego (US)
Corresponding author
Glass, Christopher K.
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2000-07-01
Volume
20
Issue
13
Pages
4699-4707
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.20.13.4699-4707.2000
PMC
PMC85890
OpenAlex
W2133941138
Cited by
377
References
5
Citations by year
2026: 5 · 2025: 2 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 11 · 2019: 7 · 2018: 7 · 2017: 10 · 2016: 10 · 2015: 6 · 2014: 9 · 2013: 9 · 2012: 14
FWCI
10.86
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
PPARγ, inducible nitric oxide synthase, transrepression, CREB-binding protein, P300, SRC-1, coactivator recruitment, NF-κB, AP-1, STAT1, interferon-gamma, lipopolysaccharide, transcriptional regulation
MeSH terms
Rosiglitazone, Animals, Binding Sites, DNA-Binding Proteins, Gene Expression Regulation, Macrophages, Mutation, Nuclear Proteins, Phosphorylation, Promoter Regions, Genetic, Recombinant Proteins, Thiazoles, Transcription Factors, Trans-Activators, Point Mutation, Receptors, Cytoplasmic and Nuclear, Nitric Oxide Synthase, Dimerization, Thiazolidinediones, CREB-Binding Protein, Mice, Histone Acetyltransferases, Nitric Oxide Synthase Type II, Nuclear Receptor Coactivator 1

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