p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen.
p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen.
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DOI：
10.1083/jcb.201908212
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发表时间：
2020-11-02
期刊：
影响因子：
--
通讯作者：
Attardi LD
中科院分区：
文献类型：
--
作者：
Valente LJ;Tarangelo A;Li AM;Naciri M;Raj N;Boutelle AM;Li Y;Mello SS;Bieging-Rolett K;DeBerardinis RJ;Ye J;Dixon SJ;Attardi LD
利用癌基因表达细胞在生理氧气条件下询问p53的功能，瓦伦特等人。表明P53缺乏症会导致一系列细胞过程的同时失调。这些发现突出了P53失活的多效性效应。人类癌症中最常见的突变基因TP53抑制肿瘤形成的机制尚不清楚。P53调控多种细胞过程，如细胞凋亡和增殖，这导致在不同的背景下对P53介导的肿瘤抑制提出了不同的细胞机制。在这里，我们问的是，在肿瘤抑制期间，P53是否可能相反地调节广泛的细胞过程。在生理氧气条件下对野生型和人类癌基因表达的野生型和p53缺失细胞的分析表明，p53缺失同时影响许多不同的细胞过程，包括细胞凋亡、基因组稳定、DNA修复、新陈代谢、迁移和侵袭。值得注意的是，一些表型只在生理氧气中被发现。在这一背景下的转录切割分析突出了被P53调节的被低估的功能，包括肌动蛋白动力学。总之，这些结果表明，在转化抑制过程中，p53同时控制着不同的细胞过程，这一方面的p53功能将为其在人类癌症中频繁失活提供一个明确的理论基础。
Using oncogene-expressing cells to interrogate p53 function under physiological oxygen conditions, Valente et al. show that p53 deficiency drives concurrent dysregulation of a range of cellular processes. These findings highlight the pleiotropic effects of p53 inactivation. The mechanisms by which TP53, the most frequently mutated gene in human cancer, suppresses tumorigenesis remain unclear. p53 modulates various cellular processes, such as apoptosis and proliferation, which has led to distinct cellular mechanisms being proposed for p53-mediated tumor suppression in different contexts. Here, we asked whether during tumor suppression p53 might instead regulate a wide range of cellular processes. Analysis of mouse and human oncogene-expressing wild-type and p53-deficient cells in physiological oxygen conditions revealed that p53 loss concurrently impacts numerous distinct cellular processes, including apoptosis, genome stabilization, DNA repair, metabolism, migration, and invasion. Notably, some phenotypes were uncovered only in physiological oxygen. Transcriptomic analysis in this setting highlighted underappreciated functions modulated by p53, including actin dynamics. Collectively, these results suggest that p53 simultaneously governs diverse cellular processes during transformation suppression, an aspect of p53 function that would provide a clear rationale for its frequent inactivation in human cancer.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
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14.9
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Babicki S;Arndt D;Marcu A;Liang Y;Grant JR;Maciejewski A;Wishart DS
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Wishart DS
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9.3
作者：
Forcina GC;Conlon M;Wells A;Cao JY;Dixon SJ
通讯作者：
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影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B