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ToxSci Advance Access originally published online on November 9, 2005
Toxicological Sciences 2006 89(2):535-546; 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

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

Joshua P. Gray1, John W. Davis, II2, Lakshmi Gopinathan, Tara L. Leas, Courtney A. Nugent and John P. Vanden Heuvel3

Department of Veterinary Sciences and Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802

Received July 12, 2005; accepted October 25, 2005

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 PPARß and {gamma} do not interact with rpL11. Cotransfection 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 cotransfection. 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.

Key Words: peroxisome proliferator-activated receptor; transcription regulation; protein–protein interaction; ribosomal protein rpL11.


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