Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage.
The inhibition of KSP causes mitotic arrest by activating the spindle assembly checkpoint. While transient inhibition of KSP leads to reversible mitotic arrest, prolonged exposure to a KSP inhibitor induces apoptosis. Induction of apoptosis by the KSP inhibitor couples with mitotic slippage. Slippage-refractory cells show resistance to KSP inhibitor-mediated lethality, whereas promotion of slippage after mitotic arrest enhances apoptosis. However, attenuation of the spindle checkpoint confers resistance to KSP inhibitor-induced apoptosis. Furthermore, sustained KSP inhibition activates the proapoptotic protein, Bax, and both activation of the spindle checkpoint and subsequent mitotic slippage are required for Bax activation. These studies indicate that in response to KSP inhibition, activation of the spindle checkpoint followed by mitotic slippage initiates apoptosis by activating Bax.
Tao
Weikang
W
Department of Cancer Research, Merck Research Laboratories, West Point, PA 19486, USA. weikang_tao@merck.com
South
Victoria J
VJ
Zhang
Yun
Y
Davide
Joseph P
JP
Farrell
Linda
L
Kohl
Nancy E
NE
Sepp-Lorenzino
Laura
L
Lobell
Robert B
RB
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018816:Genes, cdc / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D008941:Spindle Apparatus / Q000502:physiology*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; C470243:KIF11 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D051028:bcl-2-Associated X Protein; C013231:pyrroline; D011494:Protein Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D016547:Kinesins