Microtubules function

The influences of herbicides on cell division fall into two classes, ie, dismption of the mitotic sequence and inhibition of mitotic entry from interphase (G, S, G2). If ceU-cycle analyses indicate increases in abnormal mitotic figures, combined with decreases in one or more of the normal mitotic stages, the effect is upon mitosis. Mitotic effects usually involve the microtubules of the spindle apparatus in the form of spindle depolymerization, blocked tubulin synthesis, or inhibited microtubule polymerization (163). Alkaloids such as colchicine [64-86-8J,viahla.stiae [865-21-4] and vincristine [57-22-7] dismpt microtubule function (164). Colchicine prevents microtubule formation and promotes disassembly of those already present. Vinblastine and vincristine also bind to free tubulin molecules, precipitating crystalline tubulin in the cytoplasm. The capacities of these dmgs to interfere with mitotic spindles, blocking cell division, makes them useful in cancer treatment. 

Natural organic compounds (among them heterocycles) affecting microtubule functions 98YZ111. 

Some are mitosis inhibitors which affect microtubule function and hence the formation of the mitotic spindle, others are topoisomerase I and II inhibitors. 

Hoyt, M. A., Totis, L and Roberts, B. T. (1991). S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66 507-517. 

The M-hexane metabolite 2,5-hexanedione was strongly positive in an in vitro test for induction of chromosome loss in S. cerevisiae (Mayer and Goin 1994). It was suggested that this effect was due to an effect of 2,5-hexanedione on microtubule function in the yeast cells, resulting in faulty segregation of chromosomes. 

Exposure of lymphocytes to authentic N=0 did not induce a global inhibition of lymphocyte function. The cytolytic activity of alloactivated mouse splenocytes as well as a murine allospecific cytolytic T lymphocyte clone were unaffected by exposure to N=0 immediately prior to the cytotoxicity assay. Additionally, the motility of various lymphocyte populations, including Con A stimulated splenocytes, alloactivated mouse splenocytes, and a T lymphocyte clone were also unaffected by previous N=0 exposure (R. A. Hoffman, J. M. Langrehr, and R. L. Simmons, unpublished observations, 1994). Thus, brief exposure to -N=0 does not affect T lymphocyte microfilament-microtubule function nor the enzymes required to induce target cell destruction. 

In the fine structure of cells, microtubules make up fibers such as the spindle fibers that attach to centromeres of chromosomes to pull chromatids apart during mitosis and meiosis. Microtubules function in a number of cellular processes, including motility of cells and subcellular components. Microtubules assemble into tubulin, a substance that can change the shape of cells. 

Colchicine binds to tubulin and prevents its polymerization into microtubules, subsequently disrupting microtubule function. Consequently, it alters nuclear structure, intracellular transport, and cytoplasmic motility, ultimately causing cell death. Colchicine is a potent inhibitor of cellular mitosis. 

Benzimadazoles Microtubule function Differences in the target Giardia, Trichomonas... 

The ability of 2,5-HD-modified tubulin generated in vitro to alter microtubule function in an in vivo model system was verified using sea urchin zygotes. Microinjection of 2,5-HD-treated tubulin into normal sea urchin zygotes before the first mitotic cycle caused obvious abnormalities, including small spindles, abnormal chromosomal movement at anaphase, and poor cytokinesis. Depending on the protocol used, mitosis was either grossly disrupted or simply slowed (42). 

Having identified microtubule function as an in vivo molecular alteration induced by 2,5-HD, the next phase of the investigation examined unique characteristics of microtubule-dependent activity in Sertoli cells, the testicular target for toxic injury, which were susceptible to disruption. 

Nogales E. 2000. Structural insights into microtubule function. Annu. Rev. Biochem. 69 277-302... 

Vinca alkaloids (vincristine, vinblastine, vinorelbine) are derived from the periwinkle plant (Vinca rosea). These agents work by binding to tubulin at a site different than colchicine or paclitaxel. They block polymerization, which prevents the formation of the mitotic spindle, and are used as antineoplastic agents. Taxanes produce a stabilization of microtubules similar to colchicine, but by a different mechanism, and also halt cells in metaphase. Paclitaxel (taxol) is the taxane used clinically. It is derived from the bark of the pacific yew. Taxol disrupts several microtubule-based functions as completely as inhibitors of polymerization, emphasizing the importance of assembly/disassembly balance in microtubule function. Recently, it has been found that paclitaxel also binds to and inhibits the function of a protein called bcl-2, an inhibitor of one or more pathways involved in mediating apoptosis. PaclitaxeTs interference with this function promotes apoptosis in addition to its microtubule-related inhibition of cell division. 

The impairment of critical cellular functions can result in systemic toxicities such as those associated with the neuromuscular system (tremor, cardiac arrhythmia, and paralysis). renal (microtubule function), and vasculature (leaky blood vessels). A noteworthy example is the acquired long QT syndrome (LQTS) associated with blockade of cardiac ion channels (14-16). LQTS results in cardiac arrhythmias, torsade de pointes, ventricular fibrillation, and can lead to sudden death. One such ion channel is the HERG protein, respon-... 

Archer, J. E., L. R. Vega, and F. Solomon (1995). Rbl2p, a yeast protein that binds to beta-tubulin and participates in microtubule function in vivo. Cell 82, 425-434. Bhamidipati, A., S. A. Lewis, and N. J. Cowan (2000). ADP ribosylation factor-like protein 2 (Arl2) regulates the interaction of tubulin-folding cofactor D with native tubulin. J. Cell. Biol. 149, 1087-1096. 

Stearns, T., M. A. Hoyt, and D. Botstein (1990). Yeast mutants sensitive to antimicrotubule drugs define three genes that affect microtubule function. Genetics 124, 251-262. 

Smith, A. M., Archer, J. E., andSolomon, F. (1998). Regulation of tubulin polypeptides and microtubule function Luvlp [correction of Rkilp] interacts with the beta-tubulin binding protein Rbl2p. Chromosoma 107, 471-478. 

Some of the earliest studies of microtubules employed several drugs that inhibit mitosis, a cell process that depends on microtubule assembly and disassembly. Two such drugs isolated from plants, colchicine and taxol, have proved to be very powerful tools for probing microtubule function, partly because they bind only to ap-tubulin or microtubules and not to other proteins and because their concentrations in cells can be easily controlled. 

Within cells, proteins, organelles, and other membrane-limited vesicles, organelles, and proteins are frequendy transported distances of many micrometers along well-defined routes In the cytosol and delivered to particular addresses. Diffusion alone cannot account for the rate, directionality, and destinations of such transport processes. Findings from early experiments with fish-scale pigment cells and nerve cells first demonstrated that microtubules function as tracks In the Intracellular transport of various types of cargo. Eventually, two families of motor proteins—kinesins and dyneins— were found to mediate transport along microtubules. 

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