ROLE OF E2F IN CELL CYCLE CONTROL AND CANCER

David G. Johnson and Robin Schneider-Broussard

The University of Texas M. D. Anderson Cancer Center, Science Park-Research, Division, Department of Carcinogenesis, P.O. Box 389, Smithville, TX 78957

Received 4/1/98 Accepted 4/20/98

2. INTRODUCTION

E2F transcription factors play a key role in cell proliferation control by linking the activities of the cell cycle machinery with the transcriptional regulation of genes whose products are required for S-phase entry and DNA synthesis. E2F DNA-binding sites (TTTC/GG/CCGC/G) are found in the promoters of genes encoding enzymes directly involved in DNA synthesis such

as DHFR, thymidine kinase, HsOrc1, and DNA polymerase alpha (1-6). Several regulators of the cell cycle, such as cdc2, cyclin E, cyclin A, and the E2F1 gene itself also contain E2F binding sites in their promoters (5,7-12). In addition, some proto-oncogenes involved in cell proliferation, including c-myb, B-myb, c-myc, and N-myc, have been shown to be regulated by E2F (1,2,13-15). In many cases, the E2F binding sites identified in these gene promoters have been demonstrated to be critical for their cell cycle-regulated expression.

E2F factors appear to be key components in a cell cycle checkpoint that determines whether a cell will arrest in G1 or enter into S-phase. Multiple mitogenic signaling pathways, as well as growth inhibitory signals, ultimately converge upon E2F at this G1 phase checkpoint. In addition to regulating S-phase entry, E2F factors have also been implicated in regulating growth inhibition, differentiation, apoptosis and oncogenic transformation. The E2F family appears to accomplish these diverse activities through the regulated expression of distinct E2F factors and through their associations with a variety of cell cycle-regulatory proteins. Recent studies are beginning to shed light on the specific roles of the different E2F species and of the various multiprotein complexes containing E2F factors. In addition, direct links are now being made between the loss of normal E2F-dependent transcriptional control and the development of cancer.