Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress.
Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress.
复制标题
Atg7 调节 p53 活性以调节代谢应激期间的细胞周期和存活
DOI：
10.1126/science.1218395
复制
发表时间：
2012-04-13
期刊：
影响因子：
--
通讯作者：
Finkel T
中科院分区：
文献类型：
--
作者：
Lee IH;Kawai Y;Fergusson MM;Rovira II;Bishop AJ;Motoyama N;Cao L;Finkel T
营养素的撤出触发退出细胞分裂周期，诱导自噬，并最终激活细胞死亡途径。这些事件之间的关系，如果有的话，没有很好的特点。我们发现，缺乏必要的自噬基因产物Atg 7的饥饿小鼠胚胎成纤维细胞未能进行细胞周期阻滞。Atg 7不依赖于其E1样酶活性，可与肿瘤抑制因子p53结合，调节编码细胞周期抑制因子p21 CDKN 1A的基因的转录。随着代谢应激时间的延长，Atg 7的缺失导致DNA损伤增加，p53依赖性细胞凋亡增加。通过删除蛋白激酶Chk 2来抑制DNA损伤反应，部分挽救了Atg 7 −/−小鼠的出生后致死率。因此，当营养物质有限时，Atg 7调节p53依赖的细胞周期和细胞死亡途径。
Withdrawal of nutrients triggers an exit from the cell division cycle, the induction of autophagy, and eventually the activation of cell death pathways. The relation, if any, among these events is not well characterized. We found that starved mouse embryonic fibroblasts lacking the essential autophagy gene product Atg7 failed to undergo cell cycle arrest. Independent of its E1-like enzymatic activity, Atg7 could bind to the tumor suppressor p53 to regulate the transcription of the gene encoding the cell cycle inhibitor p21CDKN1A. With prolonged metabolic stress, the absence of Atg7 resulted in augmented DNA damage with increased p53-dependent apoptosis. Inhibition of the DNA damage response by deletion of the protein kinase Chk2 partially rescued postnatal lethality in Atg7−/− mice. Thus, when nutrients are limited, Atg7 regulates p53-dependent cell cycle and cell death pathways.