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.

中文翻译：

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p53 缺乏会引发生理氧中多种细胞过程的失调

TP53（人类癌症中最常见的突变基因）抑制肿瘤发生的机制仍不清楚。p53 调节各种细胞过程，例如细胞凋亡和增殖，这导致人们提出了在不同情况下 p53 介导的肿瘤抑制的不同细胞机制。在这里，我们询问在肿瘤抑制过程中 p53 是否可能调节广泛的细胞过程。对生理氧条件下表达小鼠和人类癌基因的野生型和 p53 缺陷细胞的分析表明，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、代谢、迁移和侵袭。值得注意的是，一些表型仅在生理氧中才被发现。这种情况下的转录组分析强调了 p53 调节的未被充分重视的功能，包括肌动蛋白动力学。总的来说，这些结果表明 p53 在转化抑制过程中同时控制着不同的细胞过程，这是 p53 功能的一个方面，这将为它在人类癌症中频繁失活提供明确的理由。