A Single Amino Acid Change(Asp 53→Ala53) Converts Survivin from anti-apoptotic to proapoptotic

【摘要】：正Survivin is a member of the inhibitor of apoptosis protein (IAP) family that has been implicated in both apoptosis inhibition and cell cycle control. Recently, growing attentions have been attracted due to its tumor-specific expression and potential applications in tumor therapy. However, its inhibitory mechanism and subcellular localization remain controversial. Here, we report a novel Survivin mutant Surv-D53A, which displays opposing function and distinctive subcellular distribution compared with its wild type counterpart. Surv-D53A was shown to induce apoptosis in a p53-independent fashion, indicating that tumor suppressor p53 is not involved in its apoptosis pathway. Surv-D53A was shown to markedly sensitize apoptosis induced by TRAIL, doxorubicin and RIP3. We also demonstrated that Surv-D53A localizes in cytoplasm in interphase and to midbody at telophase similar to wild-type Survivin, however, it fails to co-localize with Aurora B to centromere in metaphase as wt-Survivin. Surv-D53A mutant is less stable than wt-Survivin and is degraded by ubiquitin-proteasome pathway more rapidly. Additionally, we found that Surv-D53A could interact with wt-Survivin to form heterodimer, which may account for the loss of anti-apoptotic function of wt-Survivin. Finally, unlike wt-Survivin, Surv-D53A is unable to bind to Smac/DIABLO, which may explain the underlying mechanism for its abolishment of anti-apoptotic activity of Survivin.