Abstract：
The interaction between murine double minute 2 (MDM2) and p53, marked by transcriptional induction and feedback inhibition, orchestrates a functional loop dictating cellular fate. The functional loop comprising p53-MDM2 axis is made up of an interactome consisting of approximately 81 proteins, which are spatio-temporally regulated and involved in DNA repair mechanisms. Biochemical and genetic alterations of the interactome result in dysregulation of the p53-mdm2 axis that leads to gastrointestinal (GI) cancers. A large subset of interactome is well known and it consists of proteins that either stabilize p53 or MDM2 and proteins that target the p53-MDM2 complex for ubiquitin-mediated destruction. Upstream signaling events brought about by growth factors and chemical messengers invoke a wide variety of posttranslational modifications in p53-MDM2 axis. Biochemical changes in the transactivation domain of p53 impact the energy landscape, induce conformational switching, alter interaction potential and could change solubility of p53 to redefine its co-localization, translocation and activity. A diverse set of chemical compounds mimic physiological effectors and simulate biochemical modifications of the p53-MDM2 interactome. p53-MDM2 interactome plays a crucial role in DNA damage and repair process. Genetic aberrations in the interactome, have resulted in cancers of GI tract (pancreas, liver, colorectal, gastric, biliary, and esophageal). We present in this article a review of the overall changes in the p53-MDM2 interactors and the effectors that form an epicenter for the development of next-generation molecules for understanding and targeting GI cancers.
摘要：
小鼠双分钟2（MDM2）与p53之间的相互作用，以转录诱导和反馈抑制为标志，协调一个功能循环，决定细胞的命运。包含p53-MDM2轴的功能环由大约81种蛋白质组成的相互作用组组成，它们是时空调控的，参与DNA修复机制。相互作用组的生化和遗传改变导致p53-mdm2轴的失调，从而导致胃肠道（GI）癌症。相互作用组的一大子集是众所周知的，它由稳定p53或MDM2的蛋白质和靶向p53-MDM2复合物以进行泛素介导的破坏的蛋白质组成。由生长因子和化学信使引起的上游信号事件在p53-MDM2轴中引起多种翻译后修饰。p53反式激活域的生化变化影响了能量景观，诱导构象转换，改变相互作用电位，并可以改变p53的溶解度，以重新定义其共定位，易位和活动。一组不同的化学化合物模拟生理效应物并模拟p53-MDM2相互作用组的生化修饰。p53-MDM2相互作用组在DNA损伤和修复过程中起着至关重要的作用。相互作用组中的遗传畸变，导致胃肠道癌症(胰腺，肝脏,结直肠,胃,胆道,和食道）。我们在本文中对p53-MDM2相互作用物和效应物的整体变化进行了综述，这些效应物形成了下一代分子的中心，以了解和靶向胃肠道癌症。
