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Role for Krüppel-Like Factor 4 in Determining the Outcome of p53 Response to DNA Damage

¹ National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences; ² State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Requests for reprints: Zhihua Liu, State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Phone: 86-10-67723789; Fax: 86-10-67723789; E-mail: liuzh{at}cicams.ac.cn.

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. [Cancer Res 2009;69(21):8284–92]

Key Words: p53 • KLF4 • DNA damage • cell cycle arrest • apoptosis