The regulation of E2F by 14-3-3 proteins

The E2F family of transcription factors are key regulators of the mammalian cell cycle, integrating gene expression with cell cycle progression. Physiological E2F arises when a member of the E2F family complexes with a member of the DP family. The E2F/DP complex can be directly and indirectly regulated by a variety of proteins involved in cell cycle control including members of the RB family of tumour suppressers, members of the HAT (Histone Acetyl Transferase) family and the p53 tumour suppressor. Previous work in the laboratory has now shown that the 14-3-3 family of molecules can influence the activity of E2F. This is dependent on the ability of 14-3-3 to bind to the DPS partner. Using a DP3 mutant that was unable to bind to 14-3-3 but that retained its nuclear localisation, this study has further elucidated the role of 14-3-3 in influencing the activity of E2F. 14-3-3 can positively influence E2F-mediated cell cycle progression as well as negatively regulate the apoptotic ability of E2F. Specifically, 14-3-3 allows efficient S-phase entry as well as control over E2F-mediated apoptosis. This study suggests that this could be through the regulation of E2F/DP protein levels. The activity of 14-3-3 is dependent on its ability to bind DP3 since a mutant DP3, unable to bind 14-3-3, displays delayed S-phase entry and an enhanced ability to induce apoptosis. Interestingly, the interaction between DP3 and 14-3-3 was shown to be responsive to DNA damage, indicating that the interaction between these two proteins may be important in initiating a checkpoint control mechanism. The results presented here point to a new role for 14-3-3 in the regulation of both the cell cycle and apoptosis. This regulation is carried out through the influence of 14-3-3 over E2F, mediated by the DP3 component