Molecular mechanisms of peroxisome proliferator-activated receptor signaling Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/jw827f62b

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  • Peroxisome proliferator-activated receptors (PPARs) are members of a large group of ligand-regulated transcription factors that includes nuclear receptors for steroid and thyroid hormones, retinoids and vitamin D₃. Synthetic fibrates and thiazolidinediones that bind to and activate PPARs are used efficaciously in humans to remedy hypertriglyceridemia and non-insulin dependent diabetes mellitus, respectively. The objective of the studies described herein was to elucidate the molecular mechanisms of ligand-dependent PPAR signaling. Several PPAR ligands, including WY-14,643, were demonstrated to directly induce PPARα conformational changes as evidenced by a differential protease sensitivity assay. Conformational changes were induced in a dose-dependent manner which paralleled that of ligand to induce transcriptional activation. Direct interaction of ligands with, and the resulting conformational alterations in, PPARα may facilitate interaction of the receptor with transcriptional intermediary factors and thus may underlie the molecular basis of ligand-dependent transcriptional activation mediated by PPARα. The yeast two hybrid screen was utilized to identify downstream components of the PPARα signaling pathway. Using this technique, the coactivator proteins, p300 and steroid receptor coactivator-1 (SRC-1), were identified as PPARα-interacting proteins and WY-14,643 potentiated these interactions. p300 also enhanced the transcriptional activation properties of PPARα and, therefore, can be considered a bona fide coactivator for this nuclear receptor. Nuclear receptor corepressor (NCoR) was also isolated as a PPARα-interacting protein from a yeast two hybrid screen. In contrast to the ligand enhanced PPARα-coactivator interactions, WY-14,643 inhibited NCoR interaction with PPARα. NCoR and the coactivators, p300 and SRC-1, were also demonstrated to require distinct receptor regions for efficient interaction with PPARα. Results described herein demonstrate that ligand induces PPARα conformational changes, promotes PPARα-coactivator (p300 and SRC-1) interactions, and inhibits PPARα-NCoR interactions. We hypothesize that such molecular events are critical for ligand-dependent transcriptional activation by PPARα. These results contribute additional knowledge as to the molecular mechanisms of PPAR-dependent signaling and may act as a starting part for the improvement and/or development of therapeutic strategies aimed at manipulating this signaling pathway.
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  • description.provenance : Submitted by John Valentino (valentjo@onid.orst.edu) on 2012-09-13T19:59:48Z No. of bitstreams: 1 DowellPaulT1999.pdf: 10250863 bytes, checksum: 905deb36b19080e0019782db50730d31 (MD5)
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  • description.provenance : Approved for entry into archive by Patricia Black(patricia.black@oregonstate.edu) on 2012-09-14T17:23:04Z (GMT) No. of bitstreams: 1 DowellPaulT1999.pdf: 10250863 bytes, checksum: 905deb36b19080e0019782db50730d31 (MD5)

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