Author: ["Norbert M. Wikonkal","Eva Remenyik","Dejan Knezevic","Wengeng Zhang","Ming Liu","Hongyu Zhao","T. R. Berton","David G. Johnson","Douglas E. Brash"]
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Abstract
The E2f1 transcription factor, which regulates genes required for S-phase entry1,2,3,4, also induces apoptosis by transcriptional and post-translational mechanisms5,6,7,8. As E2f1 is inducible by DNA damage9,10 we investigated its importance in vivo in ultraviolet (UV)-induced apoptosis, a protective mechanism that prevents the epidermis from accumulating UV-induced mutations11,12. Contrary to expectation, E2f1−/− mice demonstrated enhanced keratinocyte apoptosis after UVB exposure, whereas apoptosis was suppressed by epidermis-specific overexpression of human E2F1. Apoptosis induced by γ-radiation was also repressed by E2f1. E2f1−/−;Trp53−/− double knockout mice exhibited the elevated UVB-induced apoptosis of E2f1−/− alone, rather than the profound apoptosis defect seen in Trp53−/− mice, indicating that Trp53 (p53) lies functionally upstream of E2f1. Transfecting E2F1 into E2f1−/−;Trp53−/− primary fibroblasts suppressed UVB-induced apoptosis and this suppression was relieved by Trp53. The double knockout also reverted the abnormal sex ratio and early-onset tumours of Trp53−/− mice. These results imply that E2f1 functions as a suppressor of an apoptosis pathway that is initiated by DNA photoproducts and perhaps genetic abnormalities; p53 relieves this suppression.Cite this article
Wikonkal, N., Remenyik, E., Knezevic, D. et al. Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice. Nat Cell Biol 5, 655–660 (2003). https://doi.org/10.1038/ncb1001 