Tumor formation via loss of a molecular motor protein.
Aneuploidy has long been suggested to be causal in tumor formation. Direct testing of this hypothesis has been difficult because of the absence of methods to specifically induce aneuploidy. The chromosome-associated kinesin motor KIF4 plays multiple roles in mitosis, and its loss leads to multiple mitotic defects including aneuploidy. Here, we have taken advantage of the direct formation of aneuploidy in the absence of KIF4 to determine whether loss of a molecular motor and generation of aneuploidy during mitosis can trigger tumorigenesis. We find that embryonic stem cells genetically depleted of KIF4 support anchorage-independent growth and form tumors in nude mice. In cells lacking KIF4, mitotic spindle checkpoints and DNA-damage response pathways are activated. Down regulation or loss of KIF4 is physiologically relevant because reduced KIF4 levels are present in 35% of human cancers from several tissues. Our results support the notion that loss of a molecular motor leads to tumor formation and that aneuploidy can act as a primary trigger of tumorigenesis.
Mazumdar
Manjari
M
National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. mazumbam@mail.nih.gov
Lee
Ji-Hyeon
JH
Sengupta
Kundan
K
Ried
Thomas
T
Rane
Sushil
S
Misteli
Tom
T
D000782:Aneuploidy; D000818:Animals; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D016547:Kinesins / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology
D000911:Antibodies, Monoclonal; D009419:Nerve Tissue Proteins; C089655:Kif4 protein, mouse; D016547:Kinesins