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ToxSci Advance Access originally published online on December 22, 2008
Toxicological Sciences 2009 108(1):48-58; doi:10.1093/toxsci/kfn260
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Regulation of Peroxisome Proliferator–Activated Receptor-{alpha} by MDM2

Lakshmi Gopinathan*,{dagger}, Daniel B. Hannon{dagger}, Jeffrey M. Peters{dagger} and John P. Vanden Heuvel{dagger},1

* The Huck Institutes of the Life Sciences {dagger} Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802

1 To whom correspondence should be addressed at 325 Life Sciences Building, Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802. Fax: (814) 863-1696. E-mail: jpv2{at}psu.edu.

Received October 24, 2008; accepted December 10, 2008


  Abstract

Peroxisome proliferator–activated receptor-alpha (PPAR{alpha}) belongs to the nuclear receptor (NR) family of transcription factors and regulates lipid and glucose metabolism. Like other NRs, the regulation of gene expression by PPAR{alpha} depends on cofactor recruitment to the transcription complex and multiple protein-protein interactions. In this study, Murine Double Minute 2 (MDM2), an E3 ubiquitin ligase, is identified as a PPAR{alpha}-interacting protein that regulates PPAR{alpha} transcriptional activity. MDM2 modulated the transcriptional activity of PPAR{alpha} and PPARβ/{delta}, but not PPAR{gamma} in reporter assays. Knockdown of MDM2 by small interfering RNA in rat hepatoma cells inhibited ligand-induced mRNA levels of several PPAR{alpha} target genes involved in lipid metabolism. MDM2 associated with PPAR{alpha} on target gene promoters, and this association increased in response to Wy14,643 treatment. MDM2 interacted with PPAR{alpha} and this interaction occurred with the A/B domain of PPAR{alpha}. Coexpression of MDM2 increased PPAR{alpha} ubiquitination and the E3 ubiquitin ligase activity of MDM2 affected PPAR{alpha} protein expression and transcriptional activity. MDM2 expression was decreased in response to clofibrate in wild-type (WT), but not in PPAR{alpha} null mice, indicating a PPAR{alpha}-dependent regulation. These studies identify a role for MDM2 in regulating PPAR{alpha}-mediated pathways of lipid metabolism.

Key Words: peroxisome proliferator-activated receptor alpha; MDM2; nuclear receptor.


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