The G2/M regulator 14-3-3σ prevents apoptosis through sequestration of Bax

In response to DNA damage and genotoxic stress, the p53 tumor suppressor triggers either cell cycle arrest or apoptosis. The G(2) arrest after damage is, in part, mediated by the p53 target, 14-3-3 sigma (sigma). Colorectal tumor cells lacking a are exquisitely sensitive to DNA damage. Here we analyzed the mechanism of this sensitivity in sigma (-/-) as compared with sigma (+/+) human colorectal tumor cells. Exposure to adriamycin resulted in rapid apoptosis only in sigma (-/-) cells. This was further characterized by caspase-3 activation, p21(CIP1) cleavage, and CDK2 activation. Moreover, Bax was rapidly translocated out of the cytoplasm, and cytochrome c was released in sigma (-/-) cells. Transient adenovirus-mediated reconstitution of or in the sigma (-/-) cells led to effective rescue of this phenotype and protected cells against apoptosis. The association of sigma, Bax, and CDK1 in protein complexes may be the basis for this antiapoptotic mechanism. In conclusion, a not only enforces the p53-dependent G(2) arrest but also delays the apoptotic signal transduction.