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DNA Binding-Independent Induction of IB Gene Transcription by PPAR

Institut National de la Santé et de la Recherche Médicale U.545 (P.D., J.-C.F., B.S.), Département d’Athérosclérose, Institut Pasteur de Lille, 59019 Lille, and Faculté de Pharmacie, Université de Lille II, 59000 Lille, France; Laboratory of Molecular Biology (K.D.B., W.V.B., G.H.), University of Gent and Vlaams Interuniversitair Instituut voor Biotechnologie, B-9000 Gent, Belgium

Address all correspondence and requests for reprints to: Dr. Philippe Delerive, Gene Regulation, Bone and Inflammation Research, Lilly Corporate Center, Building 98C-3 Drop Code 0434, Indianapolis, Indiana 46285. E-mail: delerive_philippe{at}lilly.com or Dr. Bart Staels, Institut National de la Santé et de la Recherche Médicale U.545, Institut Pasteur de Lille, 1 rue Calmette, BP 245, 59019 Lille, France. E-mail: Bart.Staels{at}pasteur-lille.fr.

PPARs are ligand-activated transcription factors that regulate energy homeostasis. In addition, PPARs furthermore control the inflammatory response by antagonizing the nuclear factor-B (NF-B) signaling pathway. We recently demonstrated that PPAR activators increase IB mRNA and protein levels in human aortic smooth muscle cells. Here, we studied the molecular mechanisms by which PPAR controls IB expression. Using transient transfection assays, it is demonstrated that PPAR potentiates p65-stimulated IB transcription in a ligand-dependent manner. Site-directed mutagenesis experiments revealed that PPAR activation of IB transcription requires the NF-B and Sp1 sites within IB promoter. Chromatin immunoprecipitation assays demonstrate that PPAR activation enhances the occupancy of the NF-B response element in IB promoter in vivo. Overexpression of the oncoprotein E1A failed to inhibit PPAR-mediated IB promoter induction, suggesting that cAMP response element binding protein-binding protein/p300 is not involved in this mechanism. By contrast, a dominant-negative form of VDR-interacting protein 205 (DRIP205) comprising its two LXXLL motifs completely abolished PPAR ligand-mediated activation. Furthermore, cotransfection of increasing amounts of DRIP205 relieved this inhibition, suggesting that PPAR requires DRIP205 to regulate IB promoter activity. By contrast, DRIP205 is not involved in PPAR-mediated NF-B transcriptional repression. Taken together, these data provide a molecular basis for PPAR-mediated induction of IB and demonstrate, for the first time, that PPAR may positively regulate gene transcription in the absence of functional PPAR response elements.

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