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Toxicol Sci. 2006 Feb;89(2):535-46. Epub 2005 Nov 9.

The ribosomal protein rpL11 associates with and inhibits the transcriptional activity of peroxisome proliferator-activated receptor-alpha.

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


Peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha to identify proteins involved in PP signaling. The ribosomal protein L11 (rpL11), a component of the large 60S subunit, was identified as a PPARalpha-associated protein. Since rpL11 is a regulator of p53 and the cell cycle, the association between this protein and PPARalpha was examined in detail. PPARalpha-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 PPARalpha. Unlike PPARalpha, the two closely related isoforms PPARbeta and gamma do not interact with rpL11. Cotransfection of mammalian cells with rpL11 resulted in ligand-dependent inhibition of transcriptional activity of PPARalpha. 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 PPARalpha was overexpressed by cotransfection. However, when endogenous levels of PPARalpha 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 PPARalpha activity and adds further evidence that ribosomal proteins play roles in the control of transcriptional regulation.

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