Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
Acta Biochim Biophys Sin (Shanghai). 2014 Mar;46(3):170-9. doi: 10.1093/abbs/gmt144. Epub 2013 Dec 29.
Tumor suppressor p53 plays a pivotal role in tumor suppression. p53 is the most frequently mutated gene in cancer. As a transcription factor, p53 mainly exerts its role in tumor suppression through transcriptional regulation of its downstream target genes. Thus, p53 and its target genes form a complex p53 signaling pathway to regulate a wide variety of biological processes to prevent tumorigenesis. Recent studies have revealed that in addition to apoptosis, cell cycle arrest and senescence, p53's functions in the regulation of energy metabolism and anti-oxidant defense contribute significantly to its role in tumor suppression. Studies further show that many tumor-associated mutant p53 proteins not only lose tumor suppressive functions of wild-type p53, but also gain new oncogenic activities that are independent of wild-type p53, including promoting tumor cell proliferation, survival, metabolic changes, angiogenesis, and metastasis, which are defined as mutant p53 gain-of-function. The frequent loss of wild-type p53 function and the gain-of-function of mutant p53 in human tumors make p53 an extremely attractive target for cancer therapy. Different strategies and many small-molecule drugs are being developed for the p53-based tumor therapy. Here, we review the mechanisms of p53 in tumor suppression and gain-of-function mutant p53 in tumor development, as well as the recent advances in the development of the p53-based tumor therapy.
抑癌基因 p53 在肿瘤抑制中起着关键作用。p53 是癌症中最常发生突变的基因。作为一种转录因子，p53 主要通过其下游靶基因的转录调控发挥其在肿瘤抑制中的作用。因此，p53 和其靶基因形成了一个复杂的 p53 信号通路，以调节广泛的生物过程，防止肿瘤发生。最近的研究表明，除了细胞凋亡、细胞周期阻滞和衰老外，p53 在调节能量代谢和抗氧化防御方面的功能对其在肿瘤抑制中的作用有重要贡献。研究进一步表明，许多与肿瘤相关的突变型 p53 蛋白不仅丧失了野生型 p53 的肿瘤抑制功能，而且获得了独立于野生型 p53 的新的致癌活性，包括促进肿瘤细胞增殖、存活、代谢变化、血管生成和转移，这些被定义为突变型 p53 的获得性功能。人类肿瘤中野生型 p53 功能的频繁丧失和突变型 p53 的获得性功能使 p53 成为癌症治疗的极具吸引力的靶点。目前正在开发基于 p53 的肿瘤治疗的不同策略和许多小分子药物。在这里，我们综述了 p53 在肿瘤抑制中的作用机制以及突变型 p53 在肿瘤发生发展中的获得性功能，以及基于 p53 的肿瘤治疗的最新进展。
