E2F Transcription Factors in Cancer, More than the Cell Cycle

Abstract

In the 1980s, research groups set out to identify the protein that could bind the adenovirus E2 promoter, already known to be inducible by the adenovirus E1A gene product. Joseph Nevins’ group found through gel-shift assays, DNA footprinting, and competition assays that an intrinsic cellular factor similar to E1A could bind the E2 adenoviral promoter. The first of the E2F transcription factors to be identified was E2F1, copurified with antibodies against the retinoblastoma protein (pRB). RB1 is a pocket protein and tumor suppressor known predominantly for its critical role in regulating the G1 to S-phase cell cycle entry, accomplished through sequestering E2F until phosphorylated via cyclin-dependent kinases. Other experiments showing adenovirus E1A protein could compete for pRB complexing further confirmed that pRB was a specific target of E2F transcription factors. Along with many promoters found to contain consensus sequences for E2F binding, E2F1 was later shown to induce S-phase cell cycle genes responsible for DNA synthesis, release gamma irradiated cells from G1 arrest, and, when overexpressed, induce apoptosis. Currently a total of eight E2F transcription factors have been identified, all binding to a similar consensus motif of TTTSSCGC, with S being either a G or a C in this instance. However, microarray analyses and chromatin immunoprecipitation-chip (ChIP-chip) studies have provided evidence that E2Fs can be recruited to non-consensus binding sites on core promoter regions and that many E2Fs are both degenerate in their functions and can compensate for each other. E2Fs have been grouped together based on their conserved DNA binding domains and have garnered attention for both their first identified role as integral in driving the cell cycle but gained prominence for noncanonical roles including apoptosis, DNA repair, and others. Many of these functions, both canonical and noncanonical, are important in the induction of carcinogenesis.