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Molecular mechanisms of peroxisome proliferator-activated receptor signaling

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dc.contributor.advisor Leid, Mark
dc.creator Dowell, Paul T.
dc.date.accessioned 2012-09-14T17:23:04Z
dc.date.available 2012-09-14T17:23:04Z
dc.date.copyright 1998-06-09
dc.date.issued 1998-06-09
dc.identifier.uri http://hdl.handle.net/1957/33553
dc.description Graduation date: 1999 en_US
dc.description.abstract 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. en_US
dc.language.iso en_US en_US
dc.subject.lcsh Peroxisomes en_US
dc.subject.lcsh Ligands (Biochemistry) en_US
dc.title Molecular mechanisms of peroxisome proliferator-activated receptor signaling en_US
dc.type Thesis/Dissertation en_US
dc.degree.name Doctor of Philosophy (Ph. D.) in Molecular and Cellular Biology en_US
dc.degree.level Doctoral en_US
dc.degree.discipline Interdisciplinary Studies en_US
dc.degree.grantor Oregon State University en_US
dc.contributor.committeemember Franklin, Paul
dc.contributor.committeemember Lomax, Terri
dc.contributor.committeemember Merrill, Gary
dc.contributor.committeemember Wilcox, Anthony
dc.description.digitization File scanned at 300 ppi (Monochrome, 8-bit Grayscale) using ScandAll PRO 1.8.1 on a Fi-6670 in PDF format. CVista PdfCompressor 4.0 was used for pdf compression and textual OCR. en_US
dc.description.peerreview no en_us

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