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- W2314233206 abstract "DNA damage response is essential for maintenance of genomic integrity and functions as a guardian against oncogenic transformation. Ionizing radiation and chemotherapeutic drugs used in anticancer therapies often incur DNA damage in killing of tumor cells. The central regulator of DNA damage response is the tumor suppressor p53, which inhibits cell cycle progression by activating p21 and other cell cycle regulators, or induces apoptosis through proapoptotic targets such as PUMA and Bax. In addition to p53, other p53 family members, such as p73 and p63, also play a significant role in DNA damage response. However, it has remained unclear how coordination of different p53 family members modulates DNA damage response. In this study, we found that sub-lethal levels of DNA damage up-regulated TAp73, the transcriptionally active form of p73, whereas lethal doses of DNA damage triggered TAp73 depletion. In response to mild DNA damage, TAp73 occupied p53 responsive elements in the promoters of p53 target genes to keep the transcriptional activity of p53 in check, which resulted in cell cycle arrest. Following excessive DNA damage, the depletion of TAp73 resulted in enhanced induction of p53 target genes such as PUMA, Noxa and Bax, leading to apoptosis initiation. Furthermore, our results demonstrated that TAp73 depletion after excessive DNA damage was caused by ubiquitin/proteasome-mediated degradation of E2F1, which activates TAp73 expression to maintain cell survival. Collectively, our results suggest that modulation of p53 activity by TAp73 mediates differential responses to genotoxic stress. Citation Format: Dongshi Chen, Lihua Ming, Fangdong Zou, Jian Yu, Lin Zhang. TAp73 depletion unleashes p53-mediated apoptotic response to lethal DNA damage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 777. doi:10.1158/1538-7445.AM2013-777" @default.
- W2314233206 created "2016-06-24" @default.
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- W2314233206 date "2013-04-15" @default.
- W2314233206 modified "2023-09-30" @default.
- W2314233206 title "Abstract 777: TAp73 depletion unleashes p53-mediated apoptotic response to lethal DNA damage." @default.
- W2314233206 doi "https://doi.org/10.1158/1538-7445.am2013-777" @default.
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