Mitotic spindle formation

Vinblastine and vincristine are alkaloids isolated from plants of the periwinkle family (Vinca rosea). These compounds cause cells to stop at metaphase and inhibit assembly of microtubules, and likewise, failure of mitotic spindle formations. They inhibit synthesis of nucleic acids and proteins. 

Even though early work indicated that the drug was having effects on the fungal cell wall, nucleic acid synthesis inhibition, and alterations of cytoplasmic microtubles, later studies all point toward a specific inhibition of mitotic spindle formation. 

Antineoplastic plant alkaloid cell cycle (M phase)-specific agent inhibits mitotic spindle formation. Tox peripheral neuropathy. Vinblastine, a congener, causes myelosuppression. 

Paddy, M. R., Saumweber, H., Agard, D. A., and Sedat, J. W. (1996). Time-resolved, in vivo studies of mitotic spindle formation and nuclear lamina breakdown in Drosophila early embryos. J. Cell Sci. 109,591-607. 

Figure 1.9 Identification of monastrol (an inhibitor of the normal mitotic spindle formation) and its molecular target (a molecular motor protein, kinesin, Eg5) using chemical genomics.

In a pioneering forward chemical genetic screen (whole-cell mitotic arrest assay detected by fluorescence microscopy), a cell-permeable small molecule, monastrol (Figure 1.9), was identified, as it caused inhibition of the normal mitotic spindle formation but did not affect normal tubulin formation. In subsequent studies, testing the inhibition of the formation of the mutant phenotype led to the identification of the primary molecular target in the signaling cascade, a molecular motor protein, kinesin, Eg5. Monastrol treatment showed a phenotype identical to the blocking of Eg5 function by microinjection of Eg5-specific antibodies (Kapoor et al., 2000). 

Amin, M.A., Matsunaga, S., Uchiyama, S., and Fukui, K. (2008) Nucleophosmin is required for chromosome congression, proper mitotic spindle formation, and kinetochore-microtubule attachment in HeLa cells. FEES Lett, 582, 3839-3844. 

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