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Control of apoptosis and mitotic spindle checkpoint by survivin

Abstract

Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes1, acting to preserve homeostasis and developmental morphogenesis2. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry3 and controlling ploidy (chromosome number)4, the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein5,6, survivin7, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics8. Disruption of survivin–microtubule interactions results in loss of survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer7 may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.

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Figure 1: Cell-cycle-dependent expression of survivin in G2/M.
Figure 2: Survivin–microtubule interaction.
Figure 3: Survivin–microtubule interaction is required for apoptosis inhibition.
Figure 4: Disruption of survivin–microtubule interactions induces increased caspase-3 activity in G2/M phase.

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Acknowledgements

We thank A. Villa and D. Adinolfi for assistance, and M. Osborn and K. Weber for monoclonal antibody 20C6. This work was supported by the NIH/NCI and the American Heart Association (D.C.A.), the Leukemia Research Foundation (G.A.), and Telethon and Associazione Italiana Ricerca sul Cancro (P.C.M.).

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Correspondence to Dario C. Altieri.

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Li, F., Ambrosini, G., Chu, E. et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396, 580–584 (1998). https://doi.org/10.1038/25141

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