The molecular perspective: microtubules and the taxanes.

Abstract

interlocking protein filaments. A beautiful star of microtubules, the largest of these filaments, radiates outward from the center of the cell to the cell surface. This “aster” of microtubules is the railway system of the cell. Many types of cargo are carried along these rails. The endoplasmic reticulum is pulled by molecular motor proteins along microtubules, spreading it evenly throughout the cell. Vesicles are delivered to their destinations along microtubules. And, when cells divide, the most valuable cargo of the cell is carried by microtubules. Paired copies of each of the chromosomes are attached to the ends of a doubled microtubule aster and carefully separated into the two daughter cells. The cytoskeleton, in contrast to our articulated skeleton of bones, is a dynamic structure. It is continually constructed and demolished according to the shifting needs of the cell. A typical microtubule lasts for only 10 minutes before it is disassembled and the parts used to build a new one. Microtubules are nucleated in the “microtubule-organizing center,” at the center of the cell, and then extended one piece at a time into the cytoplasm. Growth proceeds in fits and starts in a process known as “dynamic instability.” Tubules grow slowly and steadily, but are punctuated by periods of rapid disassembly, when large regions peel away from the ends. A small portion of the microtubule may break up, or the fragmentation may extend all the way back to the start, completely destroying the tubule. In special cases, such as the microtubules that support the long axons and dendrites of nerve cells, auxiliary proteins stabilize the microtubule for longer periods of time. But the dynamic structure of microtubules is essential for their everyday function in transport and cell division. Essential functions make excellent targets for toxins and for cancer chemotherapy. The central role of microtubules in cell division makes them particularly attractive. Many organisms have developed toxins that block the dynamic instability of microtubules, thus blocking the ability of the cell to divide. Two types of natural plant toxins are widely used in medicine. They have the identical result of blocking division, but achieve it in exactly opposite ways. The vinca alkaloids, such as vinblastine, vincristine, and vinorelbine, bind to the end of growing microtubules, blocking the addition of more tubulin dimers. The tubule cannot grow, but it can still disassemble, so the microtubules ultimately break down into nothing. Alternatively, the taxanes, The Molecular Perspective: Microtubules and the Taxanes