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 b etween the kinetochores of chromosomes and spindle microtubules to prevent precocious separation of sister chromatids. We have investigated the role o f human inhibitor of apoptosis protein (IAP) survivin in regulation of cell division. We demonstrate that HeLa and PtK1 cells transfected or microinje cted with survivin anti-sense oligonucleotides produce significantly more p olyploid and micronucleated progeny cells and show abortive mitosis when tr eated with spindle poisons. Furthermore, perturbation of survivin function in HeLa and PtK1 cells with anti-survivin antibodies at the beginning of mi tosis affects the normal timing of separation of sister chromatids and dist urbs the 3F3/2 phosphoepitope-recognized tension sensing mechanism of the s pindle checkpoint. This leads to premature separation of sister chromatids, which results in an uneven distribution of chromosomes between the newly f ormed progeny cells-an event associated with tumor formation in many cell t ypes. Finally, cells injected with anti-survivin antibody exit mitotic bloc k induced with microtubule drugs. Our data suggest that survivin protein ma y function within the spindle checkpoint pathway.