Journal
TOXICOLOGICAL SCIENCES
Volume 89, Issue 2, Pages 535-546Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfj040
Keywords
peroxisome proliferator-activated receptor; transcription regulation; protein-protein interaction; ribosomal protein rpL11
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Funding
- NIEHS NIH HHS [ES007799] Funding Source: Medline
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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. 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.
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