E2F-4, A NEW MEMBER OF THE E2F GENE FAMILY, HAS ONCOGENIC ACTIVITY AND ASSOCIATES WITH P107 IN-VIVO

The E2F family of transcription factors controls the expression of gen es that are involved in cell cycle regulation. E2F DNA-binding activit y is found in complex with the retinoblastoma protein, pRb, and with t he pRb-related p107 and p130. To date, cDNAs for three members of the E2F gene family have been isolated. However, all three E2Fs associate in vivo exclusively with pRb. We report here the cloning and functiona l analysis of a fourth E2F family member. E2F-4 encodes a 413-amino-ac id protein with significant homology to E2F-1. E2F-4 antibodies recogn ize a 60-kD protein in anti-p107 immunoprecipitates, indicating that E 2F-4 associates with p107 in vivo. Like the other E2Fs, E2F-4 requires DP-1 for efficient DNA binding and transcriptional activation of E2F site-containing promoters. Increased expression of E2F-4 and DP-1 in S aoS-a osteosarcoma cells causes a shift from G(1)-phase cells to S and G(2)/M-phase cells, suggesting a role for E2F-4 in regulation of cell -cycle progression. We show that expression of E2F-4 and DP-1 together with an activated ras oncogene in rat embryo fibroblasts, causes tran sformation, indicating that E2F-4 has oncogenic activity.