Ins and Outs of E2Fs

Precise control of the mitotic cell cycle is a critical feature of eukaryotic life. In humans, mutations in cell cycle regulatory genes lead to the uncontrolled cell proliferation and tumor formation associated with the most dreaded of all diseases, cancer. E2F transcription factors are key components of an elaborate mechanism of cell cycle control in higher eukaryotes. For example, the promoter regions of numerous cell cycle genes that are active during S-phase (S-phase regulatory genes and genes associated with DNA replication and cell proliferation) contain multiple E2F binding sites that are involved in the repression or activation of transcription at different stages of development and in different organs or tissues. E2F regulation involves the interaction of E2F proteins with another key cell cycle regulator, the Retinoblastoma (Rb) protein (reviewed by Harbour and Dean, 2000). The Rb gene was identified as a tumor suppressor in humans, and inherited mutations in this gene lead to the development of eye tumors (retinoblastoma) in childhood. It was found subsequently that Rb plays a fundamental role in the regulation of the cell cycle, and various other types of malignant cancer are associated with Rb mutations as well. Additionally, some DNA tumor viruses produce oncoproteins that bind and inactivate Rb. In animal cells, Rb represses transcription by binding E2F transcription factors and inhibiting their ability to activate transcription. In addition, it is believed that Rb-E2F complexes can bind to promoter regions and actively repress transcription. The activities of cyclin-dependent kinases (CDKs) and CDK inhibitors exert major control over transitions from one cell cycle phase to the next in all eukaryotes. In higher eukaryotes that contain an Rb– E2F pathway, CDK-dependent phosphorylation of Rb in mid to late G1 disrupts the binding of Rb to E2F, thereby relieving the repression of E2F-regulated genes that are required for S-phase. However, not all E2Fs are created equal, and this simple view may require revision as we discover more about the expression patterns and functions of the various E2F proteins. For example, of the six human E2Fs, E2F-1, E2F-2, and E2F-3 are involved in cell cycle progression to S-phase (Lavia and Jansen-Dürr, 1999), whereas E2F-4 and E2F-5 appear to be associated with cell cycle arrest in G 1 (Gaubatz et al., 2000), and E2F-6 lacks both transcriptional activation and Rb binding domains and is believed to act as a repressor and competitive inhibitor for E2F binding sites (Cartwright et al., 1998).