Identification of Nuclear Receptor Corepressor as a Peroxisome Proliferator-activated Receptor α Interacting Protein*

Abstract

Nuclear receptor corepressor (NCoR) was demonstrated to interact strongly with peroxisome proliferator-activated receptor α (PPARα), and PPARα ligands suppressed this interaction. In contrast to the interaction of PPARα with the coactivator protein, p300, association of the receptor with NCoR did not require any part of the PPARα ligand binding domain. NCoR was found to suppress PPARα-dependent transcriptional activation in the context of a PPARα·retinoid X receptor α (RXRα) heterodimeric complex bound to a peroxisome proliferator-responsive element in human embryonic kidney 293 cells. This repression was reversed agonists of either receptor demonstrating a functional interaction between NCoR and PPARα·RXRα heterodimeric complexes in mammalian cells. NCoR appears to influence PPARα signaling pathways and, therefore, may modulate tissue responsiveness to peroxisome proliferators.

Footnotes

  • * This work was supported by American Heart Association Grant 9640219N and National Institute of Environmental Health Science Grant ES00040.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Supported by a predoctoral fellowship from the American Foundation for Pharmaceutical Education. Current address: The Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205.

  • Established Investigator of the American Heart Association. To whom correspondence should be addressed: Laboratory of Molecular Pharmacology, College of Pharmacy, Oregon State University, Corvallis, OR 97331. Tel.: 541-737-5809; Fax: 541-737-3999; E-mail:mark.leid{at}orst.edu.

  • Abbreviations:
    PPAR
    peroxisome proliferator-activated receptor
    RXR
    retinoid X receptor
    DR1
    direct repeat separated by one nucleotide
    ETYA
    5,8,11,14-eicosatetraynoic acid
    RAR
    retinoic acid receptor
    TR
    thyroid hormone receptor
    NCoR
    nuclear receptor corepressor
    SMRT
    silencing mediator of retinoid and thyroid hormone receptors
    CBP
    CREB-binding protein
    SRC-1
    steroid receptor coactivator-1
    p/CIP
    p300/CBP-interacting protein
    mPPARα
    mouse PPARα
    ID
    interaction domain
    9-cis-RA
    9-cis-retinoic acid
    RIP13
    RXR-interacting protein 13
    GAD
    GAL4 activation domain
    PPRE
    peroxisome proliferator response element
    GST
    glutathione S-transferase
    CAT
    chloramphenicol acetyltransferase
    LBD
    ligand binding domain
    • Received January 5, 1999.
    • Revision received March 26, 1999.
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