P53-independent increase in E2F-1 expression enhances the cytotoxic effects of etoposide and of adriamycin

The transcription factor E2F-1 drives cell cycle progression at the G(1)- t o S-phase boundary; however, over-expression of E2F-1 can induce apoptosis. We show here that E2F-1 protein levels increase in human medulloblastoma, glioma, lung, colon, and bladder cancer cell lines (n=7) following treatmen t with the DNA damaging agents adriamycin etoposide. This induction of E2F- 1 occurs independently of Rb or p53 status and involves new protein synthes is. Although E2F-1 protein levels increase following DNA damage, several ge nes transcriptionally targeted by E2F-1 are not similarly induced. Rather, induction of E2F-1 in the tumor cells correlates with their sensitivity to adriamycin or to etoposide. Correspondingly, fibroblasts from E2F-1 knockou t mice are more resistant to DNA damage than cells from normal mice. Overex pression of E2F-1 protein in tumor cell lines infected with an adenovirus e ncoding wild-type E2F-1 leads to enhanced cytotoxicity following exposure t o DNA damaging agents, which results from enhanced apoptosis. The results o f this study implicate a role for E2F-1 in p53-independent cytotoxicity of chemotherapy and provide a pharmacological tool for increasing levels of th e apoptosis-inducing E2F-1 protein.