Low potency of taxol at microtubule minus ends: implications for its antimitotic and therapeutic mechanism.
In many cells, low concentrations of Taxol potently block mitosis at the transition from metaphase to anaphase, with no change in microtubule polymer mass and no microtubule bundling. Mitotic block ultimately results in apoptotic cell death and appears to be the most potent antitumor mechanism of Taxol (M. A. Jordan et al., Cancer Res. 56: 816-825, 1996). Mitotic inhibition results, at least in part, from stabilization of growing and shortening dynamics, specifically at the plus ends of microtubules, by the binding of very few Taxol molecules to the microtubule surface (M. A. Jordan et al., Proc. Natl. Acad. Sci. USA, 90: 9552-9556, 1993; W. B. Derry et al., Biochemistry, 34: 2203-2211, 1995). A number of actions of Taxol on mitotic spindle function may be due to its effects on microtubule dynamics at the minus ends of microtubules, effects that previously have not been described. Here, we determined the effects of Taxol on minus ends of purified microtubules at steady state. In contrast to the strong stabilizing effects on plus ends, substoichiometric ratios of Taxol bound to tubulin in microtubules did not affect growing, shortening, or dynamicity at minus ends. Thus, in blocked mitotic cells, Taxol can potently suppress dynamics at plus ends of spindle microtubules, whereas its impotence at minus ends permits continued microtubule depolymerization at the spindle poles. Differential effects of Taxol at opposite microtubule ends may explain Taxol's actions on spindle structure and function and its unique potent antitumor action.
Derry
W B
WB
Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, 93106, USA.
Wilson
L
L
Jordan
M A
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002417:Cattle; D007700:Kinetics; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure*; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D011485:Protein Binding; D012617:Sea Urchins; D013082:Sperm Tail / Q000648:ultrastructure; D014404:Tubulin / Q000378:metabolism*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; D017239:Paclitaxel