Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice

Abstract

The E2f1 transcription factor, which regulates genes required for S-phase entry^1,2,3,4, also induces apoptosis by transcriptional and post-translational mechanisms^5,6,7,8. As E2f1 is inducible by DNA damage^9,10 we investigated its importance in vivo in ultraviolet (UV)-induced apoptosis, a protective mechanism that prevents the epidermis from accumulating UV-induced mutations^11,12. 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.