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学科主题: 基础医学
题名:
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
作者: 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
发表日期: 2008-02-01
DOI: 10.1074/jbc.M702454200
卷: 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
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/49956
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, 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

Recommended Citation:
Wang, Haiying,Zhao, Ying,Li, Lian,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[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2008,283(5):2564-2574.
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