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 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 stimulate p19(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.
Wang
D
D
Department of Carcinogenesis, Science Park-Research Division, University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957, USA.
Russell
J L
JL
Johnson
D G
DG
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D019927:Cyclin E / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050704:E2F4 Transcription Factor; D004817:Epidermis / Q000254:growth & development; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050704:E2F4 Transcription Factor; C493754:E2f1 protein, mouse; C493763:E2f4 protein, mouse; D011506:Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF