The E2F family of transcription factors regulates cell cycle progression in part through the activation of genes important for G1 to S phase cell cycle transition.1-3
Ectopic expression of E2F proteins induce quiescent cells to enter the cell cycle, consistent with their ability to promote expression of genes required for proliferation.4
E2F regulated genes include cyclins, cyclin-dependent kinases, components of the pre-replication complex such as Mcms and Orc6, and DNA synthesis genes like DNA polymerase, topoisomerases, dihydrofolate reductase (DHFR) and thymidylate synthase (TS).
Recent work has identified the E2F1 protein as a key component of this process of gene control, and likely the key E2F activity for triggering the transition from quiescence to a proliferative state. Indeed, inhibition of E2F1 activity blocks cell cycle entry but does not affect continuing cell cycles.5, 6
Moreover, E2F1, together with Myc, has been shown to be necessary for activation of the E2F program following the stimulation of cell growth.7
The activity of E2F1 is regulated at several levels. First, E2F1, which is absent in quiescent cells, is transcriptionally induced in late G1 following mitogenic stimulation.8, 9
Second, the activity of E2F proteins can be negatively regulated in part through the association of “pocket proteins” like pRb, p107 and p130. These interactions down-regulate E2F transcription by directly blocking the transactivation domain and also by recruiting histone deacetylase complexes to modify chromatin and actively repress transcription.10
Cyclin/Cdk phosphorylation of pocket proteins following mitogenic stimulation reduces their E2F binding affinity, releasing “free” E2F to transcribe proliferative target genes.11
CDK4, cyclin D, and p16, a cyclin/CDK inhibitor, are frequently mutated or deregulated in human cancer, and these mutations have the effect of hyperphosphorylating pRb.12
Tumor promoting viruses like SV40, adeno- and papillomavirus, express proteins capable of promoting E2F dependent proliferation through binding and disruption of Rb inhibition of E2F function.13
Furthermore, mutant alleles of Rb isolated from various tumors are unable to bind E2F, suggesting an important role of this interaction in suppressing tumorigenesis.14
E2Fs clearly are key regulators of cell cycle progression during normal growth stimulation and also in human cancer where function of the RB gene, or upstream regulatory components like Cyclin/Cdks and Cdk inhibitors, has been lost through mutation.
Paradoxically, E2F1 also has the capacity to induce apoptosis, in part through induction of and cooperation with the pro-apoptotic p53 tumor suppressor.15
Although this activity has been associated with other activator E2Fs (E2F1, E2F2, E2F3), it would appear that E2F1 is the primary component involved in this process and in some circumstances, may mediate the apoptotic effect of the other E2Fs.16-18