E2F4 and E2F1 Have Similar Proliferative Properties but Different Apoptotic and Oncogenic Properties In Vivo

Abstract

Loss of retinoblastoma (Rb) tumor suppressor function, as occurs in many cancers, leads to uncontrolled proliferation, an increased propensity to undergo apoptosis, and tumorigenesis. Rb negatively regulates multiple E2F transcription factors, but the role of the different E2F family members in manifesting the cellular response to Rb inactivation is unclear. To study the effect of deregulated E2F4 activity on cell growth control and tumorigenesis, transgenic mouse lines expressing the E2F4 gene under the control of a keratin 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 localize to the nucleus and induce proliferation to an extent similar to that induced by E2F1 in transgenic tissue. Unlike E2F1, E2F4 does not induce apoptosis, and this correlates with the differential abilities of these two E2F species to stimulatep19^ARF expression in vivo. To examine the role of E2F4 in tumor development, the mouse skin two-stage carcinogenesis model was utilized. Unlike E2F1 transgenic mice, E2F4 transgenic mice developed skin tumors with a decreased latency and increased incidence compared to those characteristics in wild-type controls. These findings demonstrate that while the effects of E2F1 and E2F4 on cell proliferation in vivo are similar, their apoptotic and oncogenic properties are quite different.

ACKNOWLEDGMENTS

We are very grateful to Claudio Conti, Robin Schneider-Broussard, and Aijin Wang for advice and assistance during this work. We thank Shawnda Sanders and Michelle Gardiner for preparation of the manuscript, Dale Weiss and coworkers for animal care, Judy Ing and Chris Yone for artwork, and Jennifer Smith and Jennifer Philhower for expert technical assistance.

This work was supported by grants from the National Institutes of Health (GM56144 to D.G.J., CA 79648 to D.G.J., NIEHS Center grant ES007784, and CA16672).