I Arnal1, R H Wade. 1. Laboratoire de Microscopie Electronique Structurale, Institute de Biologie Structurale Jean-Pierre Ebel (CEA, CNRS), Grenoble, France.
Abstract
BACKGROUND: The antimitotic agent taxol is an important new drug for the treatment of certain cancers. It blocks the cell cycle in its G1 or M phases by stabilizing the microtubule cytoskeleton against depolymerization. RESULTS: We have used electron cryomicroscopy and image analysis to investigate the structure of microtubules assembled in vitro, and found that their fine structure was sensitive to the presence of taxol. The conformation of the microtubule lattice depended on whether the drug was added before or after assembly. The structure of preassembled microtubules changed only slightly when taxol was added; a larger change was observed when microtubules were assembled in the presence of the drug. In both cases, taxol-containing microtubules were stable over many days at, or below, room temperature. CONCLUSIONS: As in another recent investigation using guanylyl-(alpha,beta)-methylene-diphosphonate (a non-hydrolyzable GTP analogue), microtubule stabilization with taxol is accompanied by a conformational change in the microtubule surface lattice and, implicitly, in the tubulin dimer. We speculate that a general mechanism may underlie the stabilization of microtubules by different agents.
BACKGROUND: The antimitotic agent taxol is an important new drug for the treatment of certain cancers. It blocks the cell cycle in its G1 or M phases by stabilizing the microtubule cytoskeleton against depolymerization. RESULTS: We have used electron cryomicroscopy and image analysis to investigate the structure of microtubules assembled in vitro, and found that their fine structure was sensitive to the presence of taxol. The conformation of the microtubule lattice depended on whether the drug was added before or after assembly. The structure of preassembled microtubules changed only slightly when taxol was added; a larger change was observed when microtubules were assembled in the presence of the drug. In both cases, taxol-containing microtubules were stable over many days at, or below, room temperature. CONCLUSIONS: As in another recent investigation using guanylyl-(alpha,beta)-methylene-diphosphonate (a non-hydrolyzable GTP analogue), microtubule stabilization with taxol is accompanied by a conformational change in the microtubule surface lattice and, implicitly, in the tubulin dimer. We speculate that a general mechanism may underlie the stabilization of microtubules by different agents.
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