Human inhibitor of apoptosis protein (IAP) survivin participates in regulation of chromosome segregation and mitotic exit

A signaling cascade termed the "spindle checkpoint" monitors interactions between the kinetochores of chromosomes and spindle microtubules to prevent precocious separation of sister chromatids. We have investigated the role of human inhibitor of apoptosis protein (IAP) survivin in regulation of cell division. We demonstrate that HeLa and PtK1 cells transfected or microinjected with survivin anti-sense oligonucleotides produce significantly more polyploid and micronucleated progeny cells and show abortive mitosis when treated with spindle poisons. Furthermore, perturbation of survivin function in HeLa and PtK1 cells with anti-survivin antibodies at the beginning of mitosis affects the normal timing of separation of sister chromatids and disturbs the 3F3/2 phosphoepitope-recognized tension sensing mechanism of the spindle checkpoint. This leads to premature separation of sister chromatids, which results in an uneven distribution of chromosomes between the newly formed progeny cells-an event associated with tumor formation in many cell types. Finally, cells injected with anti-survivin antibody exit mitotic block induced with microtubule drugs. Our data suggest that survivin protein may function within the spindle checkpoint pathway.