Circadian modulation of the estrogen receptor alpha transcription

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dc.contributor.authorVilla, Linda Moniqueen
dc.contributor.committeechairFinkielstein, Carla V.en
dc.contributor.committeememberSchubot, Florian D.en
dc.contributor.committeememberSobrado, Pabloen
dc.contributor.committeememberHuckle, William R.en
dc.contributor.committeememberLazar, Iuliana M.en
dc.contributor.departmentBiologyen
dc.date.accessioned2017-04-06T15:43:09Zen
dc.date.adate2012-08-21en
dc.date.available2017-04-06T15:43:09Zen
dc.date.issued2012-07-12en
dc.date.rdate2016-09-29en
dc.date.sdate2012-07-26en
dc.description.abstractThe circadian clock is a molecular mechanism that synchronizes physiological changes with environmental variations. Disruption of the circadian clock has been linked to increased risk in diseases and a number of disorders (e.g. jet lag, insomnia, and cancer). Period 2 (Per2), a circadian protein, is at the center of the clock's function. The loss or deregulation of per2 has been shown to be common in several types of cancer including breast and ovarian [1, 2]. Epidemiological studies established a correlation between circadian disruption and the development of estrogen dependent tumors. The expression of estrogen receptor alpha (ERα) mRNA oscillates in a 24-hour period and, unlike Per2, ERα peaks during the light phase of the day. Because up regulation of ERα relates to tumor development, defining the mechanisms of ERα expression will contribute to our comprehension of cellular proliferation and regulation of normal developmental processes. The overall goal of this project is to investigate the molecular basis for circadian control of ERα transcription. Transcriptional activation of ERα was measured using a reporter system in Chinese hamster ovary (CHO) cell lines. Data show that Per2 influences ERα transcription through a non-canonical mechanism independent of its circadian counterparts. Breast cancer susceptibility protein 1 (BRCA1) was confirmed to be an interactor of Per2 via bacterial two-hybrid assays, in accordance with previous studies [2]. BRCA1 is a transcriptional activator of ERα promoter in the presence of octamer transcription factor-1 (OCT-1) [3]. Our results indicate that the DNA binding domain of OCT-1, POU, to directly interact with Per2 and BRCA1, in vitro. Pull-down assays were used to map direct interaction of various Per2 and BRCA1 recombinant proteins and POU. Chromatin immunoprecipitation assays confirmed the recruitment of PER2 and BRCA1 to the estrogen promoter by OCT-1 and the recruitment of Per2 to the ERα promoter decreases ERα mRNA expression levels in MCF-7 cells. Our work supports a circadian regulation of ERα through the repression of esr1 by Per2 in MCF-7 cells.en
dc.description.degreePh. D.en
dc.identifier.otheretd-07262012-174501en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-07262012-174501/en
dc.identifier.urihttp://hdl.handle.net/10919/77146en
dc.language.isoen_USen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectEstrogen receptor alphaen
dc.subjectoctamer transcription factor-1en
dc.subjectcircadianen
dc.subjectperiod 2en
dc.subjectbreast cancer susceptibility gene 1en
dc.titleCircadian modulation of the estrogen receptor alpha transcriptionen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineBiologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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