Chen Jiandong
Molecular Oncology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Transl Cancer Res. 2016 Dec;5(6):639-649. doi: 10.21037/tcr.2016.09.23.
The p53 tumor suppressor is highly regulated at the level of protein degradation and transcriptional activity. The key players of the pathway, p53, MDM2, and MDMX are present at multiple conformational states that are responsive to regulation by post-translational modifications and protein-protein interactions. The structures of major functional domains of these proteins have been determined, but the mechanisms of several intrinsically disordered regions remain unclear despite their critical roles in signaling and regulation. Recent studies suggest that these disordered regions function in part by dynamic intra molecular interactions with the structured domains to regulate p53 DNA binding, MDM2 ubiquitin E3 ligase activity, and MDMX-p53 binding. These findings provide new insight on how p53 is controlled by various stress signals, and suggest potential targets for the search of allosteric regulators of the p53 pathway.
p53肿瘤抑制因子在蛋白质降解和转录活性水平上受到高度调控。该信号通路的关键参与者p53、MDM2和MDMX存在多种构象状态，这些状态对翻译后修饰和蛋白质-蛋白质相互作用的调控有响应。这些蛋白质主要功能结构域的结构已被确定，但尽管几个内在无序区域在信号传导和调控中起关键作用，其机制仍不清楚。最近的研究表明，这些无序区域部分通过与结构化结构域的动态分子内相互作用来发挥功能，以调节p53与DNA的结合、MDM2泛素E3连接酶活性以及MDMX与p53的结合。这些发现为p53如何受各种应激信号控制提供了新的见解，并为寻找p53信号通路的变构调节剂提供了潜在靶点。
