Zhou Qibing, Hong Yuan, Zhan Qimin, Shen Yan, Liu Zhihua
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Cancer Res. 2009 Nov 1;69(21):8284-92. doi: 10.1158/0008-5472.CAN-09-1345. Epub 2009 Oct 13.
Cells are incessantly exposed to many sources of genotoxic stress. A critical unresolved issue is how the resulting activation of the p53 tumor suppressor can lead to either cell cycle arrest or apoptosis depending on the extent of DNA damage. The present study shows that the level of Krüppel-like factor 4 (KLF4) expression is inversely correlated with the extent of DNA damage. KLF4 is activated by p53 following cytostatic, mild DNA damage, whereas it is strongly repressed via enhanced turnover of mRNA on severe DNA damage that irreversibly drives cells to apoptosis. Blocking the repression of KLF4 on severe DNA damage suppresses p53-mediated apoptosis, whereas ablation of the KLF4 induction on mild DNA damage shifts the p53 response from cell cycle arrest to cell death. Our results suggest that coordinate regulation of KLF4 expression depending on the extent of DNA damage may be an important mechanism that dictates the life and death decisions of p53.
细胞不断暴露于多种基因毒性应激源。一个关键的未解决问题是，由此导致的p53肿瘤抑制因子激活如何根据DNA损伤的程度导致细胞周期停滞或凋亡。本研究表明，Krüppel样因子4（KLF4）的表达水平与DNA损伤程度呈负相关。在细胞生长停滞、轻度DNA损伤后，KLF4被p53激活，而在严重DNA损伤时，通过增强mRNA的周转，KLF4被强烈抑制，这会不可逆地促使细胞凋亡。在严重DNA损伤时阻断对KLF4的抑制可抑制p53介导的凋亡，而在轻度DNA损伤时消除KLF4的诱导会使p53反应从细胞周期停滞转变为细胞死亡。我们的结果表明，根据DNA损伤程度对KLF4表达进行协调调控可能是决定p53生死抉择的重要机制。
