Institute for Cancer Genetics, Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Genes Dev. 2021 Jan 1;35(1-2):59-64. doi: 10.1101/gad.340919.120. Epub 2020 Dec 10.
Here, we showed that the acetylation-defective mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all five acetylation sites (p53-5KR) diminished its remaining tumor suppression function. Moreover, the embryonic lethality caused by the deficiency of was fully rescued in the background of , but not background. p53-4KR retained the ability to suppress mTOR function but this activity was abolished in cells. Notably, the early-onset tumor formation observed in and -null mice was suppressed upon the treatment of the mTOR inhibitor. These results suggest that p53-mediated mTOR regulation plays an important role in both embryonic development and tumor suppression, independent of cell cycle arrest, senescence, apoptosis, and ferroptosis.
在这里，我们表明缺乏细胞周期阻滞、衰老、凋亡和铁死亡能力的乙酰化缺陷型小鼠易发生肿瘤，但未能发展为早发性肿瘤。通过鉴定 p53 赖氨酸 K136 上的一个新的乙酰化位点，我们发现所有五个乙酰化位点（p53-5KR）的同时突变降低了其剩余的肿瘤抑制功能。此外，在 背景下，完全挽救了 缺失引起的胚胎致死性，但在 背景下没有。p53-4KR 保留了抑制 mTOR 功能的能力，但这一活性在 细胞中被废除。值得注意的是，在 和 -null 小鼠中观察到的早发性肿瘤形成在 mTOR 抑制剂治疗后得到抑制。这些结果表明，p53 介导的 mTOR 调节在胚胎发育和肿瘤抑制中都起着重要作用，独立于细胞周期阻滞、衰老、凋亡和铁死亡。
