c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: A mechanism for oncogene-induced genetic instability
c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: A mechanism for oncogene-induced genetic instability
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DOI：
10.1016/s1097-2765(02)00520-8
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发表时间：
2002-05-01
期刊：
影响因子：
16
通讯作者：
Wahl, GM
中科院分区：
文献类型：
--
作者：
Vafa, O;Wade, M;Wahl, GM
癌基因的过度表达通过一种机制激活P53，该机制被认为涉及未知的过度增殖信号。我们确定了这些信号是否会产生代谢扰动，从而产生DNA损伤，DNA损伤是一种已知的p53诱导剂。生化、细胞学、细胞周期和全局基因表达分析表明，c-Myc的短暂激活可以在S期之前诱导正常人成纤维细胞的DNA损伤。损伤与诱导活性氧自由基(ROS)有关，但不诱导细胞凋亡。去调控的c-Myc部分抑制了P53介导的DNA损伤反应，使基因组受损的细胞进入周期，导致克隆形成能力较差。一种抗氧化剂减少了ROS，减少了DNA损伤和P53的激活，并提高了存活率。我们认为，癌基因激活可以诱导DNA损伤并超越损伤控制，从而通过遗传不稳定性加速肿瘤进展。
Oncogene overexpression activates p53 by a mechanism posited to involve uncharacterized hyperproliferative signals. We determined whether such signals produce metabolic perturbations that generate DNA damage, a known p53 inducer. Biochemical, cytological, cell cycle, and global gene expression analyses revealed that brief c-Myc activation can induce DNA damage prior to S phase in normal human fibroblasts. Damage correlated with induction of reactive oxygen species (ROS) without induction of apoptosis. Deregulated c-Myc partially disabled the p53-mediated DNA damage response, enabling cells with damaged genomes to enter the cycle, resulting in poor clonogenic survival. An antioxidant reduced ROS, decreased DNA damage and p53 activation, and improved survival. We propose that oncogene activation can induce DNA damage and override damage controls, thereby accelerating tumor progression via genetic instability.