Overexpression of Eg5 Causes Genomic Instability and Tumor Formation in Mice

Abstract

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. [Cancer Res 2007;67(21):10138-47]

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

“…It is thus possible that at least part of Nek7 À/À mitotic phenotypes are due to a disturbance in one or more of the multiple mitotic tasks performed by Eg5 (Walczak et al, 1998). Interestingly, overexpression of Eg5 in transgenic mice resulted in tetraploidization, aneuploidy and high incidence of cancers (Castillo et al, 2007). Tetraploidization has recently been suggested as a major route to aneuploidy (for review, see Storchova and Kuffer, 2008).…”

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

“…We have to note that although transient transfections in HeLa cells were successful in the period of 36 h, we were unable to raise permanently transfected clones expressing either wild type or any of the Eg5 mutants. One possible explanation for our inability to raise stable expressing clones may come from the recent observation in the mouse model showing that overexpression of Eg5 resulted in tumorogenesis which was associated with chromosome instability due to perturbations of mitotic spindle assembly [36].…”

The role of kinesin family proteins in tumorigenesis and progression

“…In nonproliferating cells and tissues in adults, the expression of KSP remains undetectable, whereas its expression is prominent in proliferating cells and tissues during development. 20,55 Increased expression of Eg5 reportedly is associated with tumorigenesis. For example, Castillo et al 20 demonstrated that transgenic mice that overexpressed Eg5 were prone to the development of a variety of tumors.…”

“…For example, alterations of KIF3, 13 KIF1B, 14 KIF14, 15 and Kid 16 proteins were observed in breast cancer; KIF14 17 and KIF4A 18 were altered in lung cancer; and KIF1B was down-regulated in neurofibroma. 19 In addition, altered expression of EG5, 20 CENP-E, 21 KIF5B, 22 and KIF18A 23 proteins was associated with the development of different human cancers. Thus, an analysis of their expression may serve as useful tools for the early detection of tumorigenesis and for better predictions of prognosis for patients with cancer.…”

“…4 To date, many studies have demonstrated that altered expression of kinesins is associated with the development and progression of various human cancers. [13][14][15][16][17][18][19][20][21][22][23] Abnormal kinesin expression alters the equal distribution of genetic materials during cell mitosis because of chromosome hypercondensation, aberrant spindle formation, anaphase bridges, defective cytokinesis, aneuploidy, Figure 1. The structure and functional domains of kinesin family proteins (KIFs) are illustrated.…”