Budanov Andrei V
Department of Neurosurgery & Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA,
Subcell Biochem. 2014;85:337-58. doi: 10.1007/978-94-017-9211-0_18.
Tumor suppressor p53 is inactivated in most cancers and the critical role of p53 in the suppression of carcinogenesis has been confirmed in many mouse models. The protein product of the tumor suppressor p53 gene works as a transcriptional regulator, activating expression of numerous genes involved in cell death, cell cycle arrest, senescence, DNA-repair and many other processes. In spite of the multiple efforts to characterize the functions of p53, the mechanisms of tumor suppression by p53 are still elusive. Recently, new activities of p53 such as regulation of reactive oxygen species (ROS) and metabolism have been described and the p53-regulated genes responsible for these functions have been identified. Metabolic derangements and accumulation of ROS are features of carcinogenesis, supporting the idea that many tumor suppressive effects of p53 can be mediated by regulation of metabolism and/or ROS. Mutations in the p53 gene can not only inactivate wild type function of p53 but also endow p53 with new functions such as activation of new metabolic pathways contributing to carcinogenesis. Understanding the metabolic and antioxidant functions of p53 allows us to develop approaches to restore p53 function in cancers, where p53 is inactivated, in other to ensure the best outcome of anti-cancer treatment.
肿瘤抑制因子p53在大多数癌症中失活，并且p53在抑制肿瘤发生中的关键作用已在许多小鼠模型中得到证实。肿瘤抑制因子p53基因的蛋白质产物作为一种转录调节因子，激活众多参与细胞死亡、细胞周期停滞、衰老、DNA修复及许多其他过程的基因的表达。尽管人们为表征p53的功能付出了诸多努力，但p53抑制肿瘤的机制仍不清楚。最近，已描述了p53的新活性，如对活性氧（ROS）和代谢的调节，并且已鉴定出负责这些功能的p53调节基因。代谢紊乱和ROS积累是肿瘤发生的特征，这支持了p53的许多肿瘤抑制作用可通过调节代谢和/或ROS来介导的观点。p53基因中的突变不仅可使p53的野生型功能失活，还可赋予p53新功能，如激活有助于肿瘤发生的新代谢途径。了解p53的代谢和抗氧化功能使我们能够开发在p53失活的癌症中恢复p53功能的方法，以确保抗癌治疗取得最佳效果。
