Exogenous E2F expression is growth inhibitory before, during, and after cellular transformation.
To gain insight into the tumor suppressor properties of E2F1, we investigated growth inhibition by the E2F family of transcription factors using a tissue culture model system. We first show that exogenous E2F expression causes an 80% decrease in NIH3T3 colony formation and activated c-Ha-Ras-mediated focus formation. Inhibition of Ras-mediated transformation was dependent upon E2F DNA binding activity but did not require amino- or carboxy-terminal E2F1 protein interaction domains. Because E2F upregulation has been suggested to be associated with a neoplastic phenotype, it was possible that increased E2F activity would not be inhibitory to previously transformed cells. However, we found that exogenous E2F was also inhibitory to growth of NIH3T3 cells previously transformed by Ras or Neu. Further characterization revealed that exogenous E2F expression is inhibitory at very early times after transfection, causing dramatic losses in transfected cell populations. Interestingly, those few cells which do establish appear to be unaffected by the overexpressed E2F. Therefore, we propose that increased E2F activity may only be tolerated in a subset of cells which have acquired specific alterations that are dominant over E2F-mediated growth inhibition.
Lee
T A
TA
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706, USA.
Farnham
P J
PJ
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D016147:Genes, Tumor Suppressor; D018734:Genes, erbB-2; D011905:Genes, ras; D051379:Mice; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics*
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors