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ToxSci Advance Access published online on December 22, 2008
Toxicological Sciences, 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}

* 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

Corresponding author: John P Vanden Heuvel, 325 Life Sciences Building, Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802. Phone: (814) 863-8532. Fax: (814) 863-1696. E-mail: jpv2{at}psu.edu

Received October 24, 2008; revision received December 8, 2008; accepted December 10, 2008


  Abstract

Peroxisome Proliferator-Activated Receptor-alpha (PPAR{alpha}) belongs to the nuclear receptor family of transcription factors and regulates lipid and glucose metabolism. Like other nuclear receptors, 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 siRNA 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 wildtype, 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.


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