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学科主题基础医学
An ATM- and Rad3-related (ATR) signaling pathway and a phosphorylation-acetylation cascade are involved in activation of p53/p21(Waf1/Cip1) in response to 5-aza-2 ′-deoxycytidine treatment
Wang, Haiying1; Zhao, Ying1; Li, Lian1; McNutt, Michael A.2; Wu, Lipeng1; Lu, Shaoli1; Yu, Yu1; Zhou, Wen1; Feng, Jingnan1; Chai, Guolin1; Yang, Yang1; Zhu, Wei-Guo1,3
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
2008-02-01
DOI10.1074/jbc.M702454200
283期:5页:2564-2574
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology
研究领域[WOS]Biochemistry & Molecular Biology
关键词[WOS]DAMAGE-INDUCED PHOSPHORYLATION ; CELL-CYCLE ARREST ; DOUBLE-STRAND BREAKS ; DNA-DAMAGE ; IONIZING-RADIATION ; P53 ACETYLATION ; TRANSCRIPTIONAL ACTIVITY ; ATAXIA-TELANGIECTASIA ; TUMOR-SUPPRESSOR ; MAMMALIAN-CELLS
英文摘要

Most agents that damage DNA act through posttranslational modifications of p53 and activate its downstream targets. However, whether cellular responses to nucleoside analogue-induced DNA damage also operate through p53 posttranslational modification has not been reported. In this study, the relationship between p53 activation and its posttranslational modifications was investigated in the human cancer cell lines A549 and HCT116 in response to 5-aza-2 ′-deoxycytidine (5-aza-CdR) or cytarabine treatment. 5-Aza-CdR induces p53 posttranslational modifications through activation of an ATM- and Rad3-related (ATR) signaling pathway, and 5-aza-CdR-induced association of replication protein A with chromatin is required for the binding of ATR to chromatin. Upon treatment with 5-aza-CdR, ATR activation is clearly associated with p53 phosphorylation at Ser(15), but not at Thr(18), Ser(20), or Ser(37). This specific p53 phosphorylation at Ser15 in turn results in acetylation of p53 at Lys(320) and Lys(373)/Lys(382) through transcriptional cofactors p300/CBP-associated factor and p300, respectively. These p53 posttranslational modifications are directly responsible for 5-aza-CdR induced p21(Waf1/Cip1) expression because the binding activity of acetylated p53 at Lys(320)/Lys(373)/ Lys(382) to the p21(Waf1/Cip1) promoter, as well as p21(Waf1/Cip1) expression itself are significantly increased after 5-aza-CdR treatment. It is of interest that p53 phosphorylation at Ser15 and acetylations at Lys(320)/Lys(373)/ Lys382 mutually interact in the 5-aza-CdR induced p21(Waf1)/(Cip1) expression shown by transfection of artificially mutated p53 expression vectors including S15A, K320R, and K373R/K382 into p53-null H1299 cells. These data taken together show for the first time that 5-aza-CdR activates the ATR signaling pathway, which elicits a specific p53 phosphorylation-acetylation cascade to induce p21(Waf1/Cip1) expression.

语种英语
WOS记录号WOS:000252622300013
引用统计
被引频次:36[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/49956
专题北京大学基础医学院_病理学系
北京大学基础医学院
作者单位1.Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100083, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100083, Peoples R China
3.Peking Univ, Hlth Sci Ctr, Canc Res Ctr, Beijing 100083, Peoples R China
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GB/T 7714
Wang, Haiying,Zhao, Ying,Li, Lian,等. An ATM- and Rad3-related (ATR) signaling pathway and a phosphorylation-acetylation cascade are involved in activation of p53/p21(Waf1/Cip1) in response to 5-aza-2 ′-deoxycytidine treatment[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2008,283(5):2564-2574.
APA Wang, Haiying.,Zhao, Ying.,Li, Lian.,McNutt, Michael A..,Wu, Lipeng.,...&Zhu, Wei-Guo.(2008).An ATM- and Rad3-related (ATR) signaling pathway and a phosphorylation-acetylation cascade are involved in activation of p53/p21(Waf1/Cip1) in response to 5-aza-2 ′-deoxycytidine treatment.JOURNAL OF BIOLOGICAL CHEMISTRY,283(5),2564-2574.
MLA Wang, Haiying,et al."An ATM- and Rad3-related (ATR) signaling pathway and a phosphorylation-acetylation cascade are involved in activation of p53/p21(Waf1/Cip1) in response to 5-aza-2 ′-deoxycytidine treatment".JOURNAL OF BIOLOGICAL CHEMISTRY 283.5(2008):2564-2574.
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