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ToxSci Advance Access published online on November 9, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj040
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 12, 2005
Accepted October 25, 2005

Systems Toxicology

The Ribosomal Protein rpL11 Associates with and Inhibits the Transcriptional Activity of Peroxisome Proliferator-Activated Receptor-{alpha}

Joshua P. Gray 1, John W. Davis II2, Lakshmi G. Gopinathan 3, Tara L. Leas 3, Courtney A. Nugent 3, and John P. Vanden Heuvel 3*

1 Department of Veterinary Sciences and Center for Molecular Toxicology and Carcinogenesis, 201 Life Sciences Building, Pennsylvania State University, University Park, PA 16802; Current address: Rutgers University, Pharmacology & Toxicology, 170 Frelinghuysen Rd., Rm. 441, EOHSI Piscataway, NJ 08854
2 Department of Veterinary Sciences and Center for Molecular Toxicology and Carcinogenesis, 201 Life Sciences Building, Pennsylvania State University, University Park, PA 16802; Current address: Pfizer Global Research & Development, World Wide Safety Sciences, 800 N Linderberg Boulevard, Creve Coeur, MO 63167
3 Department of Veterinary Sciences and Center for Molecular Toxicology and Carcinogenesis, 201 Life Sciences Building, Pennsylvania State University, University Park, PA 16802

* To whom correspondence should be addressed.
John P. Vanden Heuvel, E-mail: jpv2{at}psu.edu


  Abstract

Peroxisome Proliferator-Activated Receptor alpha (PPAR{alpha}) is a member of the nuclear receptor superfamily whose ligands, the peroxisome proliferators (PPs), are liver tumor promoters in rodents. Interaction cloning was performed using bacterially expressed PPAR{alpha} to identify proteins involved in PP signaling. The ribosomal protein L11 (rpL11), a component of the large 60S subunit, was identified as a PPAR{alpha}-associated protein. Since rpL11 is a regulator of p53 and the cell cycle, the association between this protein and PPAR{alpha} was examined in detail. PPAR{alpha}-rpL11 interaction was confirmed using yeast and mammalian two-hybrid systems as well as in vitro pull-down assays. The association with rpL11 occurs within the D-domain (hinge-region) of PPAR{alpha}. Unlike PPAR{alpha}, the two closely related isoforms PPAR{beta} and {gamma} do not interact with rpL11. Co-transfection of mammalian cells with rpL11 resulted in ligand-dependent inhibition of transcriptional activity of PPAR{alpha}. Ribosomal protein L11-mediated inhibition of gene expression is associated with decreased binding to the PPAR-response element (PPRE) DNA sequence. Release of rpL11 from the ribosome by serum deprivation or low-dose actinomycin D did not dramatically affect PPRE-driven luciferase activity when PPAR{alpha} was overexpressed by co-transfection. However, when endogenous levels of PPAR{alpha} are examined and rpL11 concentration is manipulated by expression by small interference RNA the ability of peroxisome proliferator to induce PPRE-driven reporter activity and target gene mRNA is affected. These studies show that rpL11 inhibits PPAR{alpha} activity and adds further evidence that ribosomal proteins play roles in the control of transcriptional regulation.


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