Role for Kruppel-like factor 4 in determining the outcome of p53 response to DNA damage.
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.
Zhou
Qibing
Q
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.
Hong
Yuan
Y
Zhan
Qimin
Q
Shen
Yan
Y
Liu
Zhihua
Z
D000954:Antigens, Surface; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53