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

Joshua P. Gray, John W. Davis, Lakshmi Gopinathan, Tara L. Leas, Courtney A. Nugent, John P. Vanden Heuvel

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)535-546
Number of pages12
JournalToxicological Sciences
Volume89
Issue number2
DOIs
StatePublished - Feb 2006

All Science Journal Classification (ASJC) codes

  • Toxicology

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