The G2/M Regulator 14-3-3σ Prevents Apoptosis through Sequestration of Bax

Abstract

In response to DNA damage and genotoxic stress, the p53 tumor suppressor triggers either cell cycle arrest or apoptosis. The G2 arrest after damage is, in part, mediated by the p53 target, 14-3-3σ (σ). Colorectal tumor cells lacking σ are exquisitely sensitive to DNA damage. Here we analyzed the mechanism of this sensitivity in σ-/- as compared with σ+/+ human colorectal tumor cells. Exposure to adriamycin resulted in rapid apoptosis only in σ-/- cells. This was further characterized by caspase-3 activation, p21CIP1 cleavage, and CDK2 activation. Moreover, Bax was rapidly translocated out of the cytoplasm, and cytochrome c was released in σ-/- cells. Transient adenovirus-mediated reconstitution of σ in the σ -/- cells led to effective rescue of this phenotype and protected cells against apoptosis. The association of σ, Bax, and CDK1 in protein complexes may be the basis for this antiapoptotic mechanism. In conclusion, σ not only enforces the p53-dependent G2 arrest but also delays the apoptotic signal transduction.