| Title | 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 |
| Authors | Wang, Haiying Zhao, Ying Li, Lian McNutt, Michael A. Wu, Lipeng Lu, Shaoli Yu, Yu Zhou, Wen Feng, Jingnan Chai, Guolin Yang, Yang Zhu, Wei-Guo |
| Affiliation | Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100083, Peoples R China. Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100083, Peoples R China. Peking Univ, Hlth Sci Ctr, Canc Res Ctr, Beijing 100083, Peoples R China. Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, 38 Xueyuan Rd, Beijing 100083, Peoples R China. |
| Keywords | DAMAGE-INDUCED PHOSPHORYLATION CELL-CYCLE ARREST DOUBLE-STRAND BREAKS DNA-DAMAGE IONIZING-RADIATION P53 ACETYLATION TRANSCRIPTIONAL ACTIVITY ATAXIA-TELANGIECTASIA TUMOR-SUPPRESSOR MAMMALIAN-CELLS |
| Issue Date | 2008 |
| Publisher | journal of biological chemistry |
| Citation | JOURNAL OF BIOLOGICAL CHEMISTRY.2008,283,(5),2564-2574. |
| Abstract | 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. |
| URI | http://hdl.handle.net/20.500.11897/345318 |
| ISSN | 0021-9258 |
| DOI | 10.1074/jbc.M702454200 |
| Indexed | SCI(E) EI PubMed |
| Appears in Collections: | 医学部待认领 |
