克拉斯
衰老
癌变
癌症研究
自噬
基因敲除
贝肯1
生物
癌症
细胞生物学
细胞培养
遗传学
细胞凋亡
结直肠癌
作者
Juan Li,Yang Wang,Yue Luo,Yang Liu,Yong Yi,Jinsong Li,Pan Yang,Weiyuxin Li,Wanbang You,Qingyong Hu,Zhiqiang Zhao,Yujun Zhang,Yang Cao,Lingqiang Zhang,Junying Yuan,Zhi‐Xiong Jim Xiao
标识
DOI:10.1038/s41467-022-35557-y
摘要
Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in malignant tumors derived from the Kras-driven mouse model, suggesting that KRAS oncogenic signaling would have to overcome the intrinsic senescence burden for cancer progression. Here, we show that the nuclear Beclin 1-mediated inhibition of p53-dependent senescence drives Kras-mediated tumorigenesis. KRAS activates USP5 to stabilize nuclear Beclin 1, leading to MDM2-mediated p53 protein instability. KrasG12D mice lacking Beclin 1 display retarded lung tumor growth. Knockdown of USP5 or knockout of Becn1 leads to increased senescence and reduced autophagy. Mechanistically, KRAS elevates ROS to induce USP5 homodimer formation by forming the C195 disulfide bond, resulting in stabilization and activation of USP5. Together, these results demonstrate that activation of the USP5-Beclin 1 axis is pivotal in overriding intrinsic p53-dependent senescence in Kras-driven lung cancer development.
科研通智能强力驱动
Strongly Powered by AbleSci AI