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Cover for ERRβ Splice Variants Differentially Regulate Cell Cycle Progression
dc.contributor.advisorRiggins, Rebecca Ben
dc.creatoren
dc.date.accessioned2014-08-15T17:01:13Zen
dc.date.created2014en
dc.date.issueden
dc.date.submitted01/01/2014en
dc.identifier.otherAPT-BAG: georgetown.edu.10822_709958.tar;APT-ETAG: 201b3c1cd297e5f1498c620175c8b2b9; APT-DATE: 2017-01-30_12:03:15en
dc.identifier.urien
dc.descriptionPh.D.en
dc.description.abstractOrphan receptors comprise nearly half of all members of the nuclear receptor superfamily. Despite having broad structural similarities to the classical estrogen receptors, estrogen-related receptors (ERRs) have their own unique DNA response elements and functions. In this study, we focus on two ERRβ splice variants, short form ERRβ (ERRβsf) and ERRβ2, and identify their differing roles in cell cycle regulation. Using the acyl hydrazone DY131 (a synthetic agonist of ERRβ) as a tool to modulate endogenous ERRβ function, splice-variant selective shRNA, and exogenous ERRβsf and ERRβ2 cDNAs, we differentiate between splice variant function in cell cycle regulation. We demonstrate the role of ERRβsf in mediating the G1/S checkpoint through p21. We also show ERRβsf is required for DY131-induced cellular senescence. A key novel finding of this study is that ERRβ2 can mediate a G2/M arrest. Furthermore, in the absence of ERRβ2, the G2/M arrest is reversed and ERRβsf now induces p21 and initiates a G1/S arrest. These data imply a potential dominant inhibitory role for ERRβ2 on ERRβsf. Furthermore, we demonstrate DY131 cytotoxic sensitivity is dependent on p53 status. In the absence of wild-type p53 (null or mutated), activated ERRβ2 initiates an apoptotic response. In wild-type p53, ERRβsf induces p21 in a cytoprotective response and the magnitude of cell death is lessened. This study illustrates both novel functions for ERRβ splice variants as well as evidence for splice variant interaction.en
dc.formatPDFen
dc.format.extent113 leavesen
dc.languageenen
dc.publisherGeorgetown Universityen
dc.sourceGeorgetown University-Graduate School of Arts & Sciencesen
dc.sourceTumor Biologyen
dc.subjectAlternative splicingen
dc.subjectCell Cycleen
dc.subjectDY131en
dc.subjectERRβen
dc.subjectMitotic arresten
dc.subjectp53en
dc.subject.lcshOncologyen
dc.subject.lcshCytologyen
dc.subject.otherOncologyen
dc.subject.otherCellular biologyen
dc.titleERRβ Splice Variants Differentially Regulate Cell Cycle Progressionen
dc.typethesisen
gu.embargo.lift-date2015-08-15en
gu.embargo.terms1-yearen


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