Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA.
Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA.
Oncogene. 2022 May;41(22):3039-3050. doi: 10.1038/s41388-022-02331-9. Epub 2022 Apr 29.
Although it is well-established that p53-mediated tumor suppression mainly acts through its ability in transcriptional regulation, the molecular mechanisms of this regulation are not completely understood. Among a number of regulatory modes, acetylation of p53 attracts great interests. p53 was one of the first non-histone proteins found to be functionally regulated by acetylation and deacetylation, and subsequent work has established that reversible acetylation is a general mechanism for regulation of non-histone proteins. Unlike other types of posttranslational modifications occurred during stress responses, the role of p53 acetylation has been recently validated in vivo by using the knock-in mice with both acetylation-defective and acetylation-mimicking p53 mutants. Here, we review the role of acetylation in p53-mediated activities, with a focus on which specific acetylation sites are critical for p53-dependent transcription regulation during tumor suppression and how acetylation of p53 recruits specific "readers" to execute its promoter-specific regulation of different targets. We also discuss the role of p53 acetylation in differentially regulating its classic activities in cell cycle arrest, senescence and apoptosis as well as newly identified unconventional functions such as cell metabolism and ferroptosis.
虽然 p53 介导的肿瘤抑制主要通过其转录调节能力起作用已得到充分证实，但这种调节的分子机制尚不完全清楚。在许多调节模式中，p53 的乙酰化引起了极大的关注。p53 是最早被发现通过乙酰化和去乙酰化作用来调节功能的非组蛋白之一，随后的工作已经证实，可逆乙酰化是调节非组蛋白的一种普遍机制。与在应激反应中发生的其他类型的翻译后修饰不同，最近使用具有乙酰化缺陷和乙酰化模拟 p53 突变体的基因敲入小鼠在体内验证了 p53 乙酰化的作用。在这里，我们综述了乙酰化在 p53 介导的活性中的作用，重点讨论了哪些特定的乙酰化位点对于 p53 依赖性转录调节在肿瘤抑制中的重要性，以及 p53 的乙酰化如何招募特定的“读取器”来执行其对不同靶标的启动子特异性调节。我们还讨论了 p53 乙酰化在差异调节其在细胞周期停滞、衰老和凋亡中的经典活性以及新发现的非常规功能（如细胞代谢和铁死亡）中的作用。
