title: The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells.
abstract: 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.
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Gotoh
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Marian
authors.initials: M
authors.lastname: Vila-Caballer
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Carlo S
authors.initials: CS
authors.lastname: Santos
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 finkielc@vt.edu.
authors.forename: Carla V
authors.initials: CV
authors.lastname: Finkielstein
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D005095:Exoribonucleases / Q000235:genetics; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins / Q000096:biosynthesis / Q000378:metabolism*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000097642:GADD45 Proteins
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005095:Exoribonucleases; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; C493956:CDKN1A protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C421902:PER2 protein, human; C497206:MDM2 protein, human; C413442:SFN protein, human
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