DIFFERENTIAL ACTIVITIES OF E2F FAMILY MEMBERS - UNIQUE FUNCTIONS IN REGULATING TRANSCRIPTION

Several regulators of E2F transcriptional activity, including the reti noblastoma tumor suppressor (Rb) protein, p16(Ink4a), cyclin D1, and c yclin-dependent kinase 4, have been shown to be targets for genetic al terations 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 su pported by the finding that at least some members of the E2F gene fami ly can contribute to oncogenic transformation when overexpressed. Each E2F family member can dimerize with DP proteins, bind consensus E2F s ites, and activate transcription. Several pieces of evidence suggest, however, that the various E2F species have unique functions in regulat ing transcription. We compared the abilities of E2F1, E2F4, and E2F5 t o activate transcription from a variety of gene promoters and found th at in all cases E2F1 was the most potent activator, followed by E2F4 a nd then by E2F5. Construction of chimeric proteins between E2F1 and E2 F4 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 significant ly increase the activity of E2F5. We found that, consistent with a rol e for E2F5 in transcriptional repression, E2F5's binding partner p130, like Rb, could also actively repress transcription when directly boun d to a target promoter. Mol. Carcinog. 22. 190-198, 1998. (C) 1998 Wil ey-Liss, Inc.