The Multifunctional Sorting Protein PACS-2 Regulates SIRT1-Mediated Deacetylation of p53 to Modulate p21-Dependent Cell-Cycle Arrest
作者: Katelyn M. AtkinsLaura L. ThomasJonathan Barroso-GonzálezLaurel ThomasSylvain AuclairJun YinHyeog KangJay H. ChungJimmy D. DikeakosGary Thomas
作者单位: 1Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA
2Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA
3Laboratory of Obesity and Aging Research, Genetics and Development Biology Center, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA
4Schulich School of Medicine and Dentistry, University of Western Ontario, London ON N6A 5C1, Canada
刊名: Cell Reports, 2014, Vol.8 (5), pp.1545-1557
来源数据库: Elsevier Journal
DOI: 10.1016/j.celrep.2014.07.049
原始语种摘要: Summary(#br)SIRT1 regulates the DNA damage response by deacetylating p53, thereby repressing p53 transcriptional output. Here, we demonstrate that the sorting protein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate the DNA damage response. PACS-2 knockdown cells failed to efficiently undergo p53-induced cell-cycle arrest in response to DNA damage. Accordingly, p53 acetylation was reduced both in PACS-2 knockdown cells and thymocytes from Pacs-2 −/− mice, thereby blunting induction of the cyclin-dependent kinase inhibitor p21 (CDKN1A). The SIRT1 inhibitor EX-527 or SIRT1 knockdown restored p53 acetylation and p21 induction as well as p21-dependent cell-cycle arrest in PACS-2 knockdown cells. Trafficking studies revealed that cytoplasmic PACS-2 shuttled to the nucleus,...
全文获取路径: Elsevier  (合作)
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