title: Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response.
abstract: The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5(WT) in PDCD5(-/-) MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Hyo-Kyoung
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 436-400, Korea.
authors.forename: Youngsok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Medical Convergence Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Jaesung
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Mi-Hyeon
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Lansing, Michigan 49503, USA.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Peter C W
authors.initials: PC
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D047390:Casein Kinase II / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D028884:Karyopherins / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D051017:Apoptosis Regulatory Proteins; D047390:Casein Kinase II; D006655:Histone Deacetylases; D028884:Karyopherins; D009363:Neoplasm Proteins; D046988:Proteasome Endopeptidase Complex; D016159:Tumor Suppressor Protein p53; D000099186:Histone Deacetylase 3; C527880:IPO13 protein, human; C117283:PDCD5 protein, human; C486488:Pdcd5 protein, mouse; C514744:importin 13 protein, mouse