Differential activities of E2F family members: unique functions in regulating transcription.
Several regulators of E2F transcriptional activity, including the retinoblastoma tumor suppressor (Rb) protein, p16Ink4a, cyclin D1, and cyclin-dependent kinase 4, have been shown to be targets for genetic alterations that underlie the development of human cancers. Deregulation of E2F transcription factors as a result of these genetic alterations is believed to contribute to tumor development. This hypothesis is supported by the finding that at least some members of the E2F gene family can contribute to oncogenic transformation when overexpressed. Each E2F family member can dimerize with DP proteins, bind consensus E2F sites, and activate transcription. Several pieces of evidence suggest, however, that the various E2F species have unique functions in regulating transcription. We compared the abilities of E2F1, E2F4, and E2F5 to activate transcription from a variety of gene promoters and found that in all cases E2F1 was the most potent activator, followed by E2F4 and then by E2F5. Construction of chimeric proteins between E2F1 and E2F4 demonstrated that either the carboxy terminus or the amino terminus of E2F1 could make E2F4 a more potent activator. In contrast, neither the carboxy terminus nor the amino terminus of E2F1 could significantly increase the activity of E2F5. We found that, consistent with a role for E2F5 in transcriptional repression, E2F5's binding partner p130, like Rb, could also actively repress transcription when directly bound to a target promoter.
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957, USA.
A M
AM
Pierce
R
R
Schneider-Broussard
J L
JL
Philhower
D G
DG
Johnson
D001483:Base Sequence; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; D006801:Humans; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D029701:Saccharomyces cerevisiae Proteins; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D050700:E2F5 Transcription Factor; C052130:GAL4 protein, S cerevisiae; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D011506:Proteins; C493837:RBL2 protein, human; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D029701:Saccharomyces cerevisiae Proteins; D050680:Transcription Factor DP1; D014157:Transcription Factors