Microtubules formation

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. 

Taxol s journey to the clinic was slow and arduous. Initial difficulties with aqueous solubility and lack of knowledge regarding its mechanism, of action delayed its development until 1979 when, in another seminal paper in the field, S.B.Horwitz and her collaborators disclosed their findings on the interaction of taxol with microtubules.4 Taxol s unique biological action, which includes promotion of microtubule formation and microtubule stabilization, stimulated a renewed interest in taxol as a potential drug candidate. The problem of procuring adequate supplies of taxol became even... 

Polymerase responsible for microtubule formation Electron transport system of photosystem 1... 

Colchicine (a drug used in treatment of gout) and vinblastine (a cancer chemotherapy agent) may decrease liver uptake of americium. In rats that received an intraperitoneal injection of either colchicine and vinblastine prior to an intravenous or intramuscular injection of americium citrate, liver uptake of americium was lower, relative to controls, and kidney and skeletal americium uptake were higher (Seidel 1984, 1985). The effect is thought to involve disruption of hepatic microtubule formation, which is critical to the formation and intracellular processing of lysosomes, the initial site of accumulation of americium in the liver. 

The ability of natural products to inhibition of topoisomerase and precipitate apoptosis mentioned in this chapter are two abilities among several others, of which inhibition of microtubule formation, inhibition of DNA polymerase, protein kinases, protein phosphatase and aromatase, and the use of cytokines, interleukins, and tumor necrosis factor and yet uncovered cellular targets. 

Tabon, J. Morphological bifurcations involving reaction-diffusion processes during microtubule formation. Science 1994 264 245-248. 

As noted earlier, microtubule elongation has been characterized largely with respect to the involvement of guanine nucleotides and the modes of drug inhibition of microtubule formation. There have also been a number of important studies on the influence of microtubule-associated proteins and solution variables on the kinetics and thermodynamics of microtubule self-assembly. Of these, the characterization of the so-called mitotic spindle poisons has been particularly complex because of the variety of agents and the diversity of systems studied. For this reason, we shall concentrate on the other factors affecting the elongation process. 

Vinblastine (6.73) is an antimitotic drug that prevents polymerization of tubulin (Figure 6.26). When incubated with tubulin, vinblastine complexes in a 1 1 ratio with tubulin proteins. By blocking polymerization, vinblastine prevents microtubule formation and therefore mitosis. In contrast, paclitaxel (Taxol, 6.74) and epothilone B (6.75) stabilize aggregated tubulin. As a result, in the presence of paclitaxel and epothilone B, cells form static bundles of microtubules that are nonfunctional. Vinblastine and paclitaxel are both approved for clinical use against cancer. Ixabepilone (6.76), an analogue of epothilone B (6.75), has been approved by the FDA for treatment of certain forms of breast cancer. The European Medicines Agency (EMEA) did not approve ixabepilone out of concern over severe side effects.27... 

The mechanism of action for aluminum toxicity is not known, but the element is known to compete in biological systems with cations, especially magnesium (MacDonald and Martin 1988) despite an oxidation state difference, and to bind to transferrin and citrate in the blood stream (Gannot 1986). It may also affect second messenger systems and calcium availability (Birchall and Chappell 1988), and irreversibly bind to cell nucleus components (Crapper-McLachlan 1989 Dryssen et al. 1987). Aluminum has also been shown to inhibit neuronal microtubule formation. However, much more work is needed before a mechanism can be proposed. 

Microtubule filaments are hollow cylinders made of the protein tubulin. The wall of the microtubule is made up of a helical array of alternating a- and 13-tubulin subunits. The mitotic spindle involved in separating the chromosomes during cell division is made of microtubules. Colchicine inhibits microtubule formation, whereas the anticancer agent, taxol, stabilizes microtubules and interferes with mitosis. 

E. hystolitica [203], eye drops, liniments for treatment of blepharitis [200], structure—activity [115, 116], sterilization under y-irradiation [209], effect on microtubule formation [210], as internal standard for the estimation of ursodiol in human plasma [211]... 

The five remaining compounds were specifically acting on the mitotic spindle, and did not alter its components in interphase cells. One of them in particular prevented the formation of the spindle in most mitotic cells, replacing it with a monoastral microtubule formation surrounded by chromosomes the compound (9.6, Fig. 9.3) was thus named monastrol. The authors compared monastrol effects with several published effects (21-23) related to inhibition of Eg5, a member of the BimC kinesin family, and showed monastrol to be the a selective Eg5 inhibitor (Eg5-driven microtubule motility inhibition =14 pM). This compound is both the first permeable and selective inhibitor of a specific kinesin, and may have many possible applications as a tool or as the starting point for a chemical optimization program. 

Carvalho R, Reid R, Viswanathan N, Gramajo H, Julien B. The biosynthetic genes for disorazoles, potent cytotoxic compounds 49. that disrupt microtubule formation. Gene 2005 359 91-98. 

A group of mitotic inhibitors (vinblastine, vincristine, and vinorelbine) exert their cytotoxic effects by binding to tubulin. This inhibits formation of microtubules, causing metaphase arrest. Their mechanism of action and metabolism are similar, but the antitumor spectrum, dose and clinical toxicities of vinblastine, vincristine, and vinorelbine are very different. Paclitaxel and docetaxel are also mitotic inhibitors. However, they differ from the vinca alkaloids by enhancing microtubule formation. As a result, a stable and nonfunctional microtubule is produced. 

Figure 3 A typical microtubule assembly reaction is initiated by warming a solution of ice-cold tubulin dimers to 37°C in the presence of GTP. Tubulin dimers (adjacent white and gray circles) slowly form nucleating seeds (heptameric tubulin aggregate), which catalyze a rapid phase of microtubule elongation (growing microtubule) enroute to a steady state condition of microtubule formation and destruction. The assembly reaction is monitored by measuring the change in absorbance at 350 nm. In vitro incubation of microtubules with 2,5-HD or in vivo exposure of animals to 2,5-HD followed by tubulin purification yields pyrrolylated tubulin with altered assembly behavior. 2,5-HD-modified tubulin quickly forms numerous seeds, resulting in more rapid assembly into greater numbers of shorter microtubules compared to the control.

The multiscale system also appears to be capable of providing more enhanced biological functionality, particularly for vascularization, which is favored by the interaction of ECs with the nanofibrous network.s that allow suitable cell architecture and orientation for microtubule formation. Thus, the synergistic effect of micro- and nanoscales could successfully regenerate natural tissues in vivo in the near future. Future work should focus on optimizing this process to better recapitulate key features of the native ECM, including its mechanical and biochemical properties, which would enhance the functionality of these 3D multiscale scaffolds in order to fabricate functional tissue engineered constructs. 

Interferons are generally stimulatory proteins that exert their activity through interactions with cell surface receptors, inducing cellular processes and enhancing specific gene translation (79). Interferons also regulate the expression of unique antiviral proteins such as MX protein, which alters microtubule formation and mitosis, and 2 -5 -oligoadenylate synthetase (2,5-0AS), which induces the destruction of viral RNA. 

Etoposide and teniposide are semisynthetic podophyllotoxin derivatives (see Table 124-13). Podophyllin is extracted from the mayapple or mandrake plant. Like the vinca alkaloids, podophyllin itself binds to tubulin and interferes with microtubule formation. Unlike the parent compound, however, etoposide and teniposide damage tumor cells by causing strand breakage through inhibiting topoisomerase Resistance may be caused by differences in topoisomerase II levels, by increased cell ability to repair strand breaks, or by increased levels of P-glycoproteins. Etoposide and teniposide are usually clinically cross-resistant. They are cell-cycle phase-specific and arrest cells in... 

Colchicine inhibits microtubule formation and prevents phagocytic cells from engulfing the urate crystals. 

Calcium is the third most abundant metal (after Fe and Al) in the earth s crust and the fifth most abundant element in the body (after H, O, C, and N). Of all metal ions calcium, Ca, is undoubtedly most often referred to in the biochemical literature. The Ca ion plays a vital role in many processes in living systems including muscle contraction exocytosis cell fusion, adhesion, growth and motility blood cotting microtubule formation nerve excitability membrane transport of molecules intracellular communication hormonal responses biomineralization of bone and teeth photosynthesis immune reactions and enzymatic activation and control. A number of reviews and monographs are available " . 

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