Cell cycles are halted at the transition from the G1 to S-phase(G1 checkpoint) or from the G2 to M-phase(G2 check point) after DNA damage24. In the G1 checkpoint, cyclin D1 and E regulate cell progression and provide substrate specificity to their partners, the cdks, whereas the CIP/KIP family, including p21WAF/CIP1 and p27KIP1 or the INK4 family, including p16 and p19ARF, act as inhibitors24. In the G2 checkpoint, initiation of mitotis in human cells requires the activation of M-phase-promoting factor, a complex of cdk Cdc2 and a B-typ cyclin25-27. The activity of the M-phase-promoting factor is regulated by dephoshorylation of Cdc2 and nuclear accumulation of cyclin B1 protein. The nuclear translocation of cyclin B1 is regulated by its phosphorylation, and is known to mediate its biological activity28, although how the phosphorylation of cyclin B1 leads to its nuclear translocation is still unclear. The Cdc2-cyclin B1 complex, which accumulates in the cytoplasm during S and G2 phases, translocates to the nucleus during the prophase of M phase, and thus, regulates cell cycle progression29-33.
Recently, Chan et al 34. demonstrated that 14-3-3σ, a gene originally discovered in differentiating epithelial cells and a member of the 14-3-3 protein family35-38, is markedly induced by DNA damage in the presence of wild-type p53. Introduction of exogenous 14-3-3σ into cycling cells normally sequesters cyclin B1 and Cdc2 in the cytoplasm, thus preventing the Cdc2-cyclinB complex from entering the nucleus and initiating the transition from the G2 to M phase39. Cytoplasmic localization of cyclin B1 in the interphase is determined by an amino acid sequence, referred to as the "cytoplasmic retention signal"40. Nuclear translocation of cyclin B1 is induced by disruption of the nuclear export signal (NES), a recently identified short leucine-rich sequence in the cytoplasmic retention signal region41. Intriguingly, in mitotic catastrophe seen after treatment with leptomycin B, a specific inhibitor of NES-dependent intracellular transport, cyclin B1 and Cdc2 were not sequestered in the cytoplasm34,39,42.
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