Emerging roles of E2Fs in cancer: an exit from cell cycle control

Abstract

A long-standing paradigm has been that E2F activity is tightly regulated by the RB tumour suppressor and that the disruption of this regulation leads to unscheduled progression through the cell cycle. Based on structure–function studies in vitro, the mammalian E2F family of transcription factors has been artificially subdivided into activators (E2F1–E2F3) and repressors (E2F4–E2F8). E2F1–E2F3 activators are highly redundant during development. Tumour models using RB–E2F compound-mutant mice and E2F-transgenic mice show dual roles for E2Fs in tumour promotion and suppression. These results suggest tissue-specific functions and argue against a uniform role for E2Fs in cancer. Mice lacking E2F1, E2F2 or E2F3 survive to mid gestation without global defects in the cell cycle, suggesting that the activators are not essential for normal mammalian cell proliferation. We propose that under normal conditions E2Fs do not substantially contribute to the proliferative potential of a cell. Deregulated expression or activity of most members of the E2F family has been detected in many human cancers. We propose that the requirement for certain E2F family members in proliferation under oncogenic conditions represents a recent evolutionary adaptation. RB inactivation and E2F amplification coexist in cancer. RB inactivation leads to inappropriate cell cycle progression through the deregulation of E2F function. We propose that the additional increase in E2F activity caused by amplification has cell proliferation-independent functions in cancer.