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

Human 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 p...

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Autores principales: Gotoh, Tetsuya, Vila-Caballer, Marian, Santos, Carlo S., Liu, Jingjing, Yang, Jianhua, Finkielstein, Carla V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230596/
https://www.ncbi.nlm.nih.gov/pubmed/25103245
http://dx.doi.org/10.1091/mbc.E14-05-0993
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author Gotoh, Tetsuya
Vila-Caballer, Marian
Santos, Carlo S.
Liu, Jingjing
Yang, Jianhua
Finkielstein, Carla V.
author_facet Gotoh, Tetsuya
Vila-Caballer, Marian
Santos, Carlo S.
Liu, Jingjing
Yang, Jianhua
Finkielstein, Carla V.
author_sort Gotoh, Tetsuya
collection PubMed
description Human 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.
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spelling pubmed-42305962014-12-16 The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells Gotoh, Tetsuya Vila-Caballer, Marian Santos, Carlo S. Liu, Jingjing Yang, Jianhua Finkielstein, Carla V. Mol Biol Cell Articles Human 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. The American Society for Cell Biology 2014-10-01 /pmc/articles/PMC4230596/ /pubmed/25103245 http://dx.doi.org/10.1091/mbc.E14-05-0993 Text en © 2014 Gotoh, Vila-Caballer, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Gotoh, Tetsuya
Vila-Caballer, Marian
Santos, Carlo S.
Liu, Jingjing
Yang, Jianhua
Finkielstein, Carla V.
The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells
title The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells
title_full The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells
title_fullStr The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells
title_full_unstemmed The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells
title_short The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells
title_sort circadian factor period 2 modulates p53 stability and transcriptional activity in unstressed cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230596/
https://www.ncbi.nlm.nih.gov/pubmed/25103245
http://dx.doi.org/10.1091/mbc.E14-05-0993
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