Cytoplasmic localization of programmed cell death 4 contributes to its anti-apoptotic function.

We have demonstrated that the loss of programmed cell death 4 (Pdcd4), a translation inhibitor, induces apoptosis; however, when, where, and how Pdcd4 decreases in response to apoptotic stimuli and, conversely, exerts the anti-apoptotic function within normal cells are incompletely understood. Endogenous Pdcd4 was present in both the cytoplasm and nucleus of cells that survived. In cells that had committed to die by apoptotic stimuli, cytoplasmic Pdcd4 was lost more slowly than was nuclear Pdcd4; eventually, Pdcd4 remaining in the cytoplasm was lost and then apoptotic events were induced. Treatment with leptomycin B led to blocked nuclear export of Pdcd4 in cells exposed to apoptotic stimuli, assuming its translocation from the nucleus to the cytoplasm in the early phase of apoptotic processes. In cells overexpressing Pdcd4, the protein localized exclusively cytoplasmic. Overexpression of Pdcd4 resulted in reduced incidence of apoptosis in cells exposed to apoptotic stimuli compared to control cells. In addition, the expression of Procaspase-3, which is translated from the mRNA targeted by Pdcd4, was suppressed in cells overexpressing Pdcd4. Thus, the localization of Pdcd4 to the cytoplasm may be responsible for the suppression of the target mRNA translation and apoptosis.