Microtubule Dynamics and the Cell Cycle

Microtubules and their associated proteins are cytoskeletal components that play central roles in a number of cellular processes, including mitosis, motility, and cell shape. They are formed by a guanidine triphosphate (GTP)-driven self-assembly process that is initiated by the association of alpha- and beta-tubulin. These heterodimers assemble head to tail, resulting in a spiral protofiliment. In the final step of the process the protofiliments aggregate into sheets that curl up to form the microtubule. The complex equilibria that govern the creation and destruction of microtubules are influenced by a number of cellular factors, including GTP concentration, ionic strength, temperature, and the cellular concentration of certain microtubule-associated proteins. The intricacy of this assembly process and its essential nature make the microtubules and associated proteins ideal targets for the development of cancer chemotherapies.

Microtubule inhibitors target the mitotic spindle (in contrast to other mitotic inhibitors that target nucleic acids) and arrest the cell cycle during the metaphase phase, specifically arresting mitosis at the transition from metaphase to anaphase (Figure 1).

Microtubule-targeting agents can be grouped into two classes: (1) those that inhibit the polymerization process (microtubule-destabilizing agents); and (2) those that promote the polymerization of tubulin (microtubule-stabilizing agents). Each of these two major groups will be discussed in following sections of this review. The effects of microtubule interacting agents can be observed in vitro using mammalian alpha- and beta-tubulin. Thus, data from in vitro cytotoxicity, microtubule bundling, and flow cytometry can all be used to drive medicinal chemistry efforts directed toward identifying novel potent analogs of existing microtubule interacting agents.

Figure 1 Microtubule-targeting agents' effects on cell cycle.

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