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Etiology and Pathogenesis
> Tumorigenesis
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Current Biology, Volume 16, Issue 15, 8 August 2006, Pages 1559-1564,
doi:10.1016/j.cub.2006.06.029, Available online 7 August 2006
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Abstract |
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Tumor Formation via Loss of a Molecular
Motor Protein
Manjari Mazumdar*, Ji-Hyeon
Lee, Kundan Sengupta, Thomas Ried, Sushil Rane
and Tom Misteli**
National Cancer Institute, National Institutes of Health, Bethesda,
Maryland 20892 - *Corresponding author, Email: mazumdam@mail.nih.gov;
**Corresponding author, Email: mistelit@mail.nih.gov. -- Received 17
April 2006; revised 11 June 2006; accepted 12 June 2006.
Published: August 7, 2006. Available online 7 August 2006.
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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 (1), (2), (3), (4) and (5).
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.
Author Keywords: CELLCYCLE
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Copyright © 2006 Elsevier Ltd All
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