The Oncologist, Vol. 5, No. 4, 345-346,
August 2000
© 2000 AlphaMed Press
Fundamentals of Cancer Medicine |
The Molecular Perspective: Microtubules and the Taxanes
David S. Goodsell
Correspondence:
David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu WorldWideWeb: http://www.scripps.edu/pub/goodsell
Our cells are shaped and supported by a cytoskeleton of 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, such as paclitaxel and docetaxel, stabilize microtubules, blocking the disassembly process. When treated with taxanes, cells are choked with large numbers of spurious asters forming throughout the cytoplasm.
Both the vinca alkaloids and the taxanes are large molecules with complex chemistry. The multidrug transporter (discussed in this column in The Oncologist 1999;4:428-429) is designed with these types of molecule in mind, so drug resistance can be a problem. Cancer cells overproduce the transporter and pump all of the drug outside, protecting their delicate flower of cell division from harm.
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ADDITIONAL READING:
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 Additional Reading:
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- Amos LA, Lowe J. How Taxol stabilises microtubule structure. Chem Biol 1999;6:R65-R69.
- Desai A, Mitchison TJ. Microtubule polymerization dynamics. Annu Rev Cell Biol 1997;13:83-117.
- Mandelkow EM, Mandelkow E, Milligan RA. Microtubule dynamics and microtubule caps: a time-resolved cryo-electron microscopy study. J Cell Biol 1991;114:977-991.
- Nogales E, Whittaker M, Milligan RA et al. High-resolution model of the microtubule. Cell 1999;96:79-88.
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Figure 1. Microtubule structure. Microtubules are composed of two similar proteins: alpha-tubulin (in blue) and beta-tubulin (in pink). Heterodimers of one alpha and one beta subunit assemble into a sturdy cylindrical tube. Paclitaxel (in green) binds to beta-tubulin on the inner surface, stabilizing the microtubule and blocking the normal dynamics of assembly and disassembly. Atomic coordinates were taken from entry 1tub at the Protein Data Bank.
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Figure 2. Microtubule dynamics. The assembly and disassembly of tubulin heterodimers (shown here as dumbbell-shaped molecules) into microtubules are controlled by GTP (guanosine triphosphate) molecules bound to the beta-tubulin subunits (individual GTP molecules are not shown in this illustration). A tubulin heterodimer with GTP bound will add to a growing microtubule. Then, over time, the GTP is cleaved to form GDP, making the tubulin dimer less stable within the microtubule. But, as long as there is a cap of tubulin with GTP at the growing end, the microtubule as a whole will remain stable. But, if the GTP is cleaved at the end, a catastrophic disassembly will occur, as shown at the left. At any given time, about half of the tubulin in a cell will be assembled into microtubules.
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