Mirzayans Razmik, Andrais Bonnie, Kumar Piyush, Murray David
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada.
Int J Mol Sci. 2017 Apr 28;18(5):928. doi: 10.3390/ijms18050928.
Our genomes are subject to potentially deleterious alterations resulting from endogenous sources (e.g., cellular metabolism, routine errors in DNA replication and recombination), exogenous sources (e.g., radiation, chemical agents), and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an intricate network of pathways that serve to recognize the DNA damage, activate cell cycle checkpoints and facilitate DNA repair, or eliminate highly injured cells from the proliferating population. The wild-type p53 tumor suppressor and its downstream effector p21 (p21) are key regulators of these responses. Although extensively studied for its ability to control cell cycle progression, p21 has emerged as a multifunctional protein capable of downregulating p53, suppressing apoptosis, and orchestrating prolonged growth arrest through stress-induced premature senescence. Studies with solid tumors and solid tumor-derived cell lines have revealed that such growth-arrested cancer cells remain viable, secrete growth-promoting factors, and can give rise to progeny with stem-cell-like properties. This article provides an overview of the mechanisms by which p53 signaling suppresses apoptosis following genotoxic stress, facilitating repair of genomic injury under physiological conditions but having the potential to promote tumor regrowth in response to cancer chemotherapy.
我们的基因组会受到内源性因素（如细胞代谢、DNA复制和重组中的常规错误）、外源性因素（如辐射、化学试剂）以及医学诊断和治疗应用所导致的潜在有害改变的影响。基因组完整性和细胞稳态通过一个复杂的通路网络得以维持，这些通路用于识别DNA损伤、激活细胞周期检查点并促进DNA修复，或者从增殖群体中清除严重受损的细胞。野生型p53肿瘤抑制因子及其下游效应因子p21是这些反应的关键调节因子。尽管p21因其控制细胞周期进程的能力而被广泛研究，但它已成为一种多功能蛋白，能够下调p53、抑制细胞凋亡，并通过应激诱导的早衰来协调长期的生长停滞。对实体瘤和实体瘤衍生细胞系的研究表明，这种生长停滞的癌细胞仍然存活，分泌促进生长的因子，并能产生具有干细胞样特性的后代。本文概述了p53信号通路在基因毒性应激后抑制细胞凋亡的机制，该机制在生理条件下促进基因组损伤的修复，但在癌症化疗后有可能促进肿瘤再生。
