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.
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Acknowledgements
We thank C. Adrada and M. Zhu for technical assistance, C. Zeiss for histopathology, R. Tarone for statistical analysis and R. Carbone, D. Pradhan, R. Halaban and B. Kacinski for advice. This work was supported by National Institutes of Health grant CA55737 to D. E. B, CA079648 to D. G. J. and GM59507 to H.Z.
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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
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DOI: https://doi.org/10.1038/ncb1001
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