Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint.
A compromised mitotic checkpoint, the primary mechanism for ensuring that each new cell receives one copy of every chromosome, has been implicated as a contributor to carcinogenesis. However, a checkpoint response is shown here to be essential for cell survival, including that of chromosomally instable colorectal cancer cells. Reducing the levels of the checkpoint proteins BubR1 or Mad2 in human cancer cells or inhibiting BubR1 kinase activity provokes apoptotic cell death within six divisions except when cytokinesis is also inhibited. Thus, suppression of mitotic checkpoint signaling is invariably lethal as the consequence of massive chromosome loss, findings that have implications for inhibiting proliferation of tumor cells.
Kops
Geert J P L
GJ
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670, USA.
Foltz
Daniel R
DR
Cleveland
Don W
DW
D000782:Aneuploidy; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D001973:Bromodeoxyuridine / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D064246:Mad2 Proteins; D008938:Mitosis / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins; D015398:Signal Transduction; D014162:Transfection
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D001973:Bromodeoxyuridine