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Pleiotropic cell-division defects and apoptosis induced by interference with survivin function

Abstract

Here we investigate the role of the control of apoptosis in normal cell division. We show that interference with the expression or function of the apoptosis inhibitor survivin causes caspase-dependent cell death in the G2/M phase of the cell cycle, and a cell-division defect characterized by centrosome dysregulation, multipolar mitotic spindles and multinucleated, polyploid cells. Use of a dominant-negative survivin mutant or antisense survivin complementary DNA disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21Waf1/Cip1 within centrosomes, and results in caspase-dependent cleavage of p21. Polyploidy induced by survivin antagonists is accentuated in p21-deficient cells, and corrected by exogenous expression of p21. These findings show that control of apoptosis and preservation of p21 integrity within centrosomes by survivin are required for normal mitotic progression.

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Figure 1: Effect of a survivin antisense oligonucleotide on nuclear morphology and ploidy.
Figure 2: Effect of survivin targeting on cell viability and nuclear morphology.
Figure 3: Pleiotropic cell-division defects induced by survivin targeting.
Figure 4: Supramolecular assembly of apoptosis-regulating proteins within centrosomes.
Figure 5: Localization of p21Waf1/Cip1 within centrosomes.
Figure 6: Requirement of p21Waf1/Cip1 for control of ploidy by survivin.

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Acknowledgements

We thank H. Zhang for p21Waf1/Cip1 cDNA; B. Vogelstein for p21 wild-type and p21-deficient HCT116 cells; and E. Koller and L. Cowsert for technical assistance with survivin antisense oligonucleotides. This work was supported by NIH grants CA78810 and HL54131 (to D.C.A.), by the Telethon and Associazione Italiana Ricerca sul Cancro (P.C.M.), and by an Established Investigatorship Award from the American Heart Association (to D.C.A.).

Correspondence and requests for materials should be addressed to D.C.A.

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Correspondence to Dario C. Altieri.

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Li, F., Ackermann, E., Bennett, C. et al. Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1, 461–466 (1999). https://doi.org/10.1038/70242

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