TXR1-mediated thrombospondin repression: a novel mechanism of resistance to taxanes?
- Netherlands Cancer Institute, Division of Molecular Genetics and Centre of Biomedical Genetics, 1066 CX Amsterdam, The Netherlands
This extract was created in the absence of an abstract.
The usefulness of chemotherapeutic agents for the clinical treatment of cancer relies on their toxic effects on dividing cells. While most anti-cancer drugs directly affect DNA synthesis or integrity, the vinca-alkaloids and taxanes act by disrupting the cellular microtubule network (depicted schematically in Fig. 1; for review, see Zhou and Giannakakou 2005). In addition to providing structural integrity as part of the cytoskeleton, microtubules function as the cell’s freeway system by providing the infrastructure along which cargo can be transported by motor proteins such as kinesin and dynein. During cell division, microtubules are critically important for the formation of the mitotic spindle, which dictates the proper segregation of chromosomes during mitosis.
Microtubules are instrumental in maintaining cell viability. (A) Microtubules, which point with their plus end away from the centrosome from which they originate, have important roles during different phases of the cell cycle. In interphase, the microtubule network provides the cell with a system along which proteins, vesicles, and organelles can be transported by dedicated motor proteins. Kinesin transports cargo toward the plus end, whereas dynein walks along the microtubules toward the minus end of the microtubules. During mitosis, microtubules form the mitotic spindle, which is required for the faithful segregation of sister chromatids to opposite ends of the cell. Only after the spindle checkpoint has been passed and the spindle is properly resolved, cells are able to undergo cytokinesis to give rise to two daughter cells, each containing a diploid set of chromosomes. (B) Microtubules are highly dynamic. (Left) Microtubules can be conceived as hollow fiber-like structures, which are composed of 13 filaments. Each filament is a tubulin polymer, with alternating α- and β-tubulin subunits. New tubulin subunits are added to the plus end of the microtubule, whereas degradation occurs on the minus end. The regulation of …
