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Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response

 Hyo-Kyoung Choi  ;  Youngsok Choi  ;  Eun Sung Park  ;  Soo-Yeon Park  ;  Seung-Hyun Lee  ;  Jaesung Seo  ;  Mi-Hyeon Jeong  ;  Jae-Wook Jeong  ;  Jae-Ho Jeong  ;  Peter C.W. Lee  ;  Kyung-Chul Choi  ;  Ho-Geun Yoon 
 NATURE COMMUNICATIONS, Vol.6(7390) : 1-17, 2015 
Journal Title
Issue Date
Animals ; Apoptosis Regulatory Proteins/genetics* ; Casein Kinase II/metabolism ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; DNA Damage/genetics* ; Fibroblasts/metabolism* ; Gene Expression Profiling ; HCT116 Cells ; Histone Deacetylases/metabolism* ; Humans ; Immunoprecipitation ; In Situ Nick-End Labeling ; Karyopherins/metabolism ; Mass Spectrometry ; Mice ; Mice, Knockout ; Neoplasm Proteins/genetics* ; Neoplasm Transplantation ; Phosphorylation ; Prognosis ; Proteasome Endopeptidase Complex ; Real-Time Polymerase Chain Reaction ; Stomach Neoplasms/genetics* ; Stomach Neoplasms/metabolism ; Tumor Suppressor Protein p53/metabolism*
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.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Park, Soo Yeon(박수연) ORCID logo https://orcid.org/0000-0003-3743-9554
Seo, Jae Sung(서재성)
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
Lee, Seung Hyun(이승현) ORCID logo https://orcid.org/0000-0001-7549-9430
Jeong, Mi Hyeon(정미현)
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
Choi, Hyo Kyoung(최효경)
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