The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells

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dc.contributor.authorGotoh, Testuyaen
dc.contributor.authorVila-Caballer, Marianen
dc.contributor.authorSantos, Carlos S.en
dc.contributor.authorLiu, Jingjingen
dc.contributor.authorYang, Jianhuaen
dc.contributor.authorFinkielstein, Carla V.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2019-06-26T13:08:43Zen
dc.date.available2019-06-26T13:08:43Zen
dc.date.issued2014-10-01en
dc.description.abstractHuman Period 2 (hPer2) is a transcriptional regulator at the core of the circadian clock mechanism that is responsible for generating the negative feedback loop that sustains the clock. Its relevance to human disease is underlined by alterations in its function that affect numerous biochemical and physiological processes. When absent, it results in the development of various cancers and an increase in the cell’s susceptibility to genotoxic stress. Thus we sought to define a yet-uncharacterized checkpoint node in which circadian components integrate environmental stress signals to the DNA-damage response. We found that hPer2 binds the C-terminal half of human p53 (hp53) and forms a stable trimeric complex with hp53’s negative regulator, Mdm2. We determined that hPer2 binding to hp53 prevents Mdm2 from being ubiquitinated and targeting hp53 by the proteasome. Down-regulation of hPer2 expression directly affects hp53 levels, whereas its overexpression influences both hp53 protein stability and transcription of targeted genes. Overall our findings place hPer2 directly at the heart of the hp53-mediated response by ensuring that basal levels of hp53 are available to precondition the cell when a rapid, hp53-mediated, transcriptional response is needed.en
dc.description.sponsorshipThis work was supported by a National Science Foundation CAREER Award (MCB-0844491), the Avon Foundation (02-2009-033), the Fralin Life Science Institute (F441598), and the Susan G. Komen Foundation (BCTR0706931) to C.V.F.en
dc.identifier.doihttps://doi.org/10.1091/mbc.e14-05-0993en
dc.identifier.urihttp://hdl.handle.net/10919/90661en
dc.identifier.volume25en
dc.language.isoenen
dc.publisherAmerican Society for Cell Biologyen
dc.rightsCreative Commons Attribution-NonCommercial-ShareAlike 3.0 Unporteden
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/en
dc.titleThe circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cellsen
dc.title.serialMolecular Biology of the Cellen
dc.typeArticle - Refereeden

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