Infectious Diseases Unit, Sheba Medical Center, 5265601, Tel-Hashomer, Israel.
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002, Ramat-Gan, Israel.
J Mol Med (Berl). 2020 Mar;98(3):437-449. doi: 10.1007/s00109-020-01884-0. Epub 2020 Feb 4.
The onco-suppressor p53 protein plays also an important role in the control of various aspects of health and disease. p53 levels are low in normal cells and elevated under stress conditions. While low levels of p53 promote tumor formation, overactive p53 leads to premature aging and cell death. RNA degradation is a critical level of regulation contributing to the control of gene expression. p53, as an RNA-binding protein, exerts 3' → 5' exoribonuclease activity, mediating degradation of adenylate/uridylate-rich elements (ARE)-containing ssRNAs. The 3'-UTR of p53-mRNA, which is a target of p53 itself, harbors cis-acting AREs. Our results suggest that p53 controls its own expression through murine double-minute 2 (mdm2)-independent "RNA decay" function in cytoplasm. We demonstrate that p53 expresses an exoribonuclease activity through the binding to ARE sequences of p53-mRNA via translation-independent and translation-dependent polysome-associated pathways. Antagonistic interplay was detected between p53 levels and execution of its exoribonuclease function mirrored in low p53 levels in normal cells, due to the efficient exoribonuclease activity, and in the accumulation of p53 in cells exposed to p53-activating drugs in accordance with the reduced exoribonuclease activity. Apparently, p53, via control of its own mRNA stability and/or translation in cytoplasm, might act as a negative regulator of p53-mRNA levels. The observed connection between exoribonuclease activity and p53 abundance highlights the importance of this function affecting p53 expression, imperative for multiple functions, with implications for the steady-state levels of protein and for the p53 stress response. The modulation in expression of exoribonuclease activity would be translated into the alterations in p53 level. KEY MESSAGES: p53 controls its own expression through mdm2-independent "RNA decay" function in cytoplasm. p53 expresses an exoribonuclease activity through the binding to ARE sequences of p53-mRNA. Antagonistic interplay exists between stress-induced p53 and execution of its exoribonuclease function.
抑癌蛋白 p53 也在控制健康和疾病的各个方面中发挥着重要作用。p53 在正常细胞中水平较低，而在应激条件下升高。虽然低水平的 p53 促进肿瘤形成，但过度活跃的 p53 会导致过早衰老和细胞死亡。RNA 降解是一种关键的调控水平，有助于控制基因表达。p53 作为一种 RNA 结合蛋白，发挥 3'→5'外切核酸酶活性，介导富含腺苷酸/尿苷酸的元件 (ARE) 的 ssRNA 的降解。p53-mRNA 的 3'-UTR 是 p53 自身的靶标，含有顺式作用的 ARE。我们的结果表明，p53 通过在细胞质中独立于鼠双微体 2 (mdm2) 的“RNA 降解”功能来控制自身表达。我们证明，p53 通过与 p53-mRNA 的 ARE 序列结合，通过翻译独立和翻译依赖的多核糖体相关途径表达外切核酸酶活性。p53 水平与执行其外切核酸酶功能之间存在拮抗相互作用，在正常细胞中由于高效的外切核酸酶活性，p53 水平较低，而在暴露于 p53 激活药物的细胞中，p53 积累，这与外切核酸酶活性降低一致。显然，p53 通过控制其自身 mRNA 的稳定性和/或在细胞质中的翻译，可能作为 p53-mRNA 水平的负调节剂。外切核酸酶活性与 p53 丰度之间的观察到的联系突出了该功能对 p53 表达的重要性，对多种功能至关重要，对蛋白质的稳定水平和 p53 应激反应都有影响。外切核酸酶活性表达的调节将转化为 p53 水平的变化。关键信息：p53 通过在细胞质中独立于 mdm2 的“RNA 降解”功能来控制自身表达。p53 通过与 p53-mRNA 的 ARE 序列结合来表达外切核酸酶活性。应激诱导的 p53 与执行其外切核酸酶功能之间存在拮抗相互作用。
