Pleiotropic cell-division defects and apoptosis induced by interference with survivin function.
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.
Li
F
F
Boyer Center for Molecular Medicine, Department of Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.
Ackermann
E J
EJ
Bennett
C F
CF
Rothermel
A L
AL
Plescia
J
J
Tognin
S
S
Villa
A
A
Marchisio
P C
PC
Altieri
D C
DC
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D018385:Centrosome / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005799:Genes, Dominant / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011123:Polyploidy; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008941:Spindle Apparatus / Q000737:chemistry / Q000378:metabolism; D000077022:Survivin; D014162:Transfection
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; D016376:Oligonucleotides, Antisense; D011506:Proteins; D000077022:Survivin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases