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Overexpression of Eg5 causes genomic instability and tumor formation in mice.

Cancer research | Nov 1, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17974955

Proper chromosome segregation in eukaryotes is driven by a complex superstructure called the mitotic spindle. Assembly, maintenance, and function of the spindle depend on centrosome migration, organization of microtubule arrays, and force generation by microtubule motors. Spindle pole migration and elongation are controlled by the unique balance of forces generated by antagonistic molecular motors that act upon microtubules of the mitotic spindle. Defects in components of this complex structure have been shown to lead to chromosome missegregation and genomic instability. Here, we show that overexpression of Eg5, a member of the Bim-C class of kinesin-related proteins, leads to disruption of normal spindle development, as we observe both monopolar and multipolar spindles in Eg5 transgenic mice. Our findings show that perturbation of the mitotic spindle leads to chromosomal missegregation and the accumulation of tetraploid cells. Aging of these mice revealed a higher incidence of tumor formation with a mixed array of tumor types appearing in mice ages 3 to 30 months with the mean age of 20 months. Analysis of the tumors revealed widespread aneuploidy and genetic instability, both hallmarks of nearly all solid tumors. Together with previous findings, our results indicate that Eg5 overexpression disrupts the unique balance of forces associated with normal spindle assembly and function, and thereby leads to the development of spindle defects, genetic instability, and tumors.

Pubmed ID: 17974955 RIS Download

Mesh terms: Animals | Chromosome Segregation | DNA, Neoplasm | Genomic Instability | Kinesin | Mice | Mice, Transgenic | Neoplasms, Experimental | Proto-Oncogene Proteins c-pim-1 | Reverse Transcriptase Polymerase Chain Reaction | Spindle Apparatus

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Associated grants

  • Agency: NCI NIH HHS, Id: P30-CA16086
  • Agency: NCI NIH HHS, Id: R01 CA63229
  • Agency: NIGMS NIH HHS, Id: R25 GM56929
  • Agency: NICHD NIH HHS, Id: U01 HD39372
  • Agency: NCRR NIH HHS, Id: U42 RR014817-06A1
  • Agency: Intramural NIH HHS, Id:

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