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学科主题: 基础医学
题名:
The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage
作者: Wang, Haiying1; Zhou, Wen1; Zheng, Zhixing1; Zhang, Ping1; Tu, Bo1; He, Qihua2,3; Zhu, Wei-Guo1
关键词: Depsipeptide ; DNA damage ; ROS ; p53
刊名: DNA REPAIR
发表日期: 2012-02-01
DOI: 10.1016/j.dnarep.2011.10.014
卷: 11, 期:2, 页:146-156
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Genetics & Heredity ; Toxicology
研究领域[WOS]: Genetics & Heredity ; Toxicology
关键词[WOS]: HISTONE DEACETYLASE INHIBITORS ; PHOSPHORYLATION-ACETYLATION CASCADE ; LUNG-CANCER CELLS ; HUMAN P53 ; ATAXIA-TELANGIECTASIA ; THIOREDOXIN REDUCTASE ; IONIZING-RADIATION ; OXIDATIVE STRESS ; PROTEIN-KINASE ; POSTTRANSLATIONAL MODIFICATION
英文摘要:

Histone deacetylase (HDAC) inhibitors have been proven to be effective therapeutic agents to kill cancer cells through inhibiting HDAC activity or altering the structure of chromatin. As a potent HDAC inhibitor, depsipeptide not only modulates histone deacetylation but also activates non-histone protein p53 to inhibit cancer cell growth. However, the mechanism of depsipeptide-induced p53 transactivity remains unknown. Here, we show that depsipeptide causes DNA damage through induction of reactive oxygen species (ROS) generation, as demonstrated by a comet assay and by detection of the phosphorylation of H2AX. Depsipeptide induced oxidative stress was confirmed to relate to a disturbance in reduction-oxidation (redox) reactions through inhibition of the transactivation of thioredoxin reductase (TrxR) in human cancer cells. Upon treatment with depsipeptide, p53 phosphorylation at threonine 18 (Thr18) was specifically induced. Furthermore, we also demonstrated that phosphorylation of p53 at Thr18 is required for p53 acetylation at lysine 373/382 and for p21 expression in response to depsipeptide treatment. Our results demonstrate that depsipeptide plays an anti-neoplastic role by generating ROS to elicit p53/p21 pathway activation. (C) 2011 Elsevier B.V. All rights reserved.

语种: 英语
所属项目编号: 31071117 ; 90919030 ; 31070691 ; 30921062 ; 2011CB504200
项目资助者: National Natural Science Foundation of China ; Ministry of Science and Technology of China ; Beijing Natural Scicence Foundation
WOS记录号: WOS:000301618900007
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/49874
Appears in Collections:基础医学院_病理学系_期刊论文

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作者单位: 1.Peking Univ, Hlth Sci Ctr, Key Lab Carcinogenesis & Translat Res, Minist Educ,Dept Biochem & Mol Biol, Beijing 100191, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100191, Peoples R China
3.Peking Univ, Hlth Sci Ctr, Biomed Teaching Lab Ctr, Beijing 100191, Peoples R China

Recommended Citation:
Wang, Haiying,Zhou, Wen,Zheng, Zhixing,et al. The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage[J]. DNA REPAIR,2012,11(2):146-156.
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