| The E2F family of transcription factors is comprised of nine active members to date, which activate or repress genes. Well-studied members, such as E2F1 and E2F4, are known to play key roles in G1/S transition, S-phase progression, and mitosis. E2F1 is generally regarded as a transcriptional activator and E2F4 is a transcriptional repressor; the balance of their expression levels may promote apoptosis or cell cycle arrest, respectively. Functioning together with or independently of p53 in cell cycle regulation, E2F1, has been implicated in G1 cell cycle arrest following DNA damage; they share similar target genes.; Retinoblastoma (Rb) and related pocket proteins p130 and p107 play important roles in cell cycle control. However, because of multiple interacting partners, their specific roles have not been clear. Following genotoxic stress, p130 interacts with E2F4. An ionizing radiation-induced G2-phase arrest was characterized by decreased expression of MPM-2, a mitosis marker, and Cyclins A2 (early G2) and B1 (late G2 and M). Concomitant with this G2-arrest, E2F4 cellular localization was redirected to the nucleus, similar to that of p130. Knock-down of E2F4 by siRNA elicited persistent cellular DNA damage and sensitization following irradiation. Flow cytometry analyses revealed an increased population of cells with an apparent S-phase content following this treatment, but these cells were not actively dividing. Downstream E2F4 targets potentially involved in the exit from G2 arrest were identified by expression-profiling. Chromatin immunoprecipitation localized E2F4 at promoter regions of the Bub3 and Pttg1 genes following irradiation.; This work indicates that E2F4 expression, nuclear localization, and target gene repression following irradiation play crucial roles in mediating the exit from G2 arrest in cells that sustain irreparable DNA damage. As the E2F4/p130 complex has been implicated in G0 control, its translocation leading to the repression of genes with G2/M function is novel. In addition to increasing the knowledge for understanding cell cycle arrest, new insights into the treatment of prostate cancers, which in aggressive forms harbor comparatively high levels of E2F4 indicate that the regulation of E2F4 functions in a manner that can lead to resistance to therapies that traditionally target cell cycle events. |
