E2F4 and E2F1 have similar proliferative properties but different apoptotic and oncogenic properties in vivo

Loss of retinoblastoma (Rb) tumor suppressor function, as occurs in many ca ncers, leads to uncontrolled proliferation, an increased propensity to unde rgo apoptosis, and tumorigenesis. Rb negatively regulates multiple E2F tran scription factors, but the role of the different E2F family members in mani festing the cellular response to Rb inactivation is unclear. To study the e ffect of deregulated E2F4 activity on cell growth control and tumorigenesis , transgenic mouse lines expressing the E2F4 gene under the control of a ke ratin 5 (K5) promoter were developed, and their phenotypes were compared to those of previously generated K5 E2F1 transgenic mice. In contrast to what has been observed in vitro, ectopically expressed E2F4 was found to locali ze to the nucleus and induce proliferation to an extent similar to that ind uced by E2F1 in transgenic tissue. Unlike E2F1, E2F4 does not induce apopto sis, and this correlates with the differential abilities of these two E2F s pecies to stimulate p19(ARF) expression in vivo. To examine the role of E2F 4 in tumor development, the mouse skin two-stage carcinogenesis model was u tilized. Unlike E2F1 transgenic mice, E2F4 transgenic mice developed skin t umors with a decreased latency and increased incidence compared to those ch aracteristics in wild-type controls. These findings demonstrate that while the effects of E2F1 and E2F4 on cell proliferation in vivo are similar, the ir apoptotic and oncogenic properties are quite different.