Cell division and cell survival in the absence of survivin.
The survivin protein contains structural features of the inhibitor of apoptosis protein family. Previous studies have suggested that survivin is essential for cell survival because it counteracts an otherwise constitutive propensity to apoptosis during mitosis. In addition, survivin appears to be a component of the chromosomal passenger protein complex that participates in multiple facets of cell division. Here we report that euploid human cells do not die in the absence of survivin. Instead, depletion of survivin caused defects in cell division, followed by an arrest of DNA synthesis due to activation of a checkpoint involving the tumor suppressor protein p53. During anaphase mitosis in survivin-deficient cells, sister chromatids disjoined normally, but one or more of the sister chromatids frequently lagged behind the main mass of segregating chromosomes, probably because of merotelic kinetochore attachments. Survivin-deficient cells initiated but failed to complete cytokinesis, apparently because the spindle midzone and midbody microtublues were absent during late mitosis. The abnormalities of both chromosome segregation and cytokinesis could be attributed to a defect in the chromosomal passenger protein complex, with a consequent mislocalization of the kinesin-like motor protein MKLP-1 playing a more immediate role in the microtubule abnormalities. Depletion of another chromosomal passenger protein, aurora-B, recapitulated the survivin RNA interference phenotypes. We conclude that survivin can be essential for the proliferation of normal human cells by virtue of its contributions to accurate sister chromatid segregation and assembly/stabilization of microtubules in late mitosis. However, the protein is not inevitably required for the survival of normal cells.
Yang
Dun
D
G. W. Hooper Research Foundation and Department of Microbiology and Immunology, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA. dyang20@itsa.ucsf.edu
Welm
Alana
A
Bishop
J Michael
JM
D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000502:physiology*; D002503:Centromere / Q000473:pathology; D023902:Chromosome Pairing; D002877:Chromosomes, Human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D009363:Neoplasm Proteins; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism; D011003:Ploidies; D034622:RNA Interference; D008941:Spindle Apparatus / Q000378:metabolism; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D004247:DNA