Microtubule-depolymerization

Fig. 5. Kinetics of brain microtubule depolymerization following rapid dilution. (A) Time course of the disassembly reaction with experimental data represented by the data points and the theoretical progress curve indicated by the solid line. (The inset to A shows that the process can be fitted to a simple decaying exponential for part of the depolymerization reaction.) (B) Microtubule length distribution for the sample subjected to rapid dilution in A. (Reproduced from Karr et al. (1980)./. Biol. Chm. 255, 8560-8566.)...

Figure 1. Mixing device for microtubule depolymerization kinetic studies requiring prompt dilution while minimizing shearing forces that may alter the polymer length distribution.

Figure 2. Progress curve for dilution-induced microtubule depolymerization. Inset Polymer length distribution prior to dilution-induced disassembly. The data points are experimentally determined, and the solid line is based on the theoretical treatmenF. ...

The above theory can be extended to deal with other more complex cases. For example, the two ends of a biopolymer need not behave identically, and, as noted earher, MTs are helical polymers of asymmetric protomer units. Thus, two sets of on- and off-constants might be necessary. In other cases, such as in the polymerization of tubulin in the presence of tubulin-colchicine complex (Sternlicht et one may need to consider copolymerization. The kinetics of microtubule depolymerization are the reverse of elongation, and are gener-... 

Microtubule depolymerization, DEPOLYMERIZATION, END-WISE MICROTUBULE TREADMILLING... 

The formation of the neurite-like processes appears to be dependent on assembly of microtubules as colchicine and Colcemid, antimicrotubule drugs, prevented shape changes in the presence of butyrate (2,8). The amount of tubulin per cell did not change when HeLa were treated with butyrate (R.C.Henneberry, unpublished observations). The role of microtubule assembly was further explored with a calcium ionophore which alters intracellular calcium levels and thus promotes microtubule depolymerization. 

Shipley, K., Hekmat-Nejad, M., Turner, J., Moores, C., Anderson, R., Milligan, R., Sakowicz, R., and Fletterick, R. (2004). Structure of a kinesin microtubule depolymerization machine. EMBOJ. 23, 1422-1432. 

Paclitaxel and docetaxel have been shown to act as spindle poisons, causing cell division cycle arrest, based on a unique mechanism of action.7-10 These drugs bind to the P-subunit of the tubulin heterodimer, the key constituent protein of cellular microtubules (spindles). The binding of these drugs accelerates the tubulin polymerization, but at the same time stabilizes the resultant microtubules, thereby inhibiting their depolymerization. The inhibition of microtubule depolymerization between the prophase and anaphase of mitosis results in the arrest of the cell division cycle, which eventually leads to the apoptosis of cancer cells. 

Kobayashi, J. Hosoyama, H. Wang, X.-X. Shigemori, H. Koiso, Y. IwasaM, S. Sasaki, T Naito, M. Tsumo, T. Effects of taxoids from Taxus cuspidata on microtubule depolymerization and vincristin accumulation in MDR cells. Bioorg. Med Chem. Lett., 1997, 7 393-398. 

Klar, U. Graf, H. Schenk, O. Rohr, B. Schulz, H. New synthetic inhibitors of microtubule depolymerization. Bioorg. Med. Chem. Lett., 1998, 8 1397-1402. 

Actively transported PEI/DNA nanocomplexes exhibited an average velocity of 0.2 pm/sec [118], a value on the same order of magnitude as motor-protein driven motion. Transport was revealed to be microtubule dependent, because both active transport and perinuclear accumulation were abolished upon microtubule depolymerization. Experiments utilizing MPT to quantify the other intracellular barriers to gene delivery are under way. 

An example of particular interest is epothilone from Sorangium cellulosum So ce90, which has recentiy been approved for the treatment of breast cancer. Epothilone inhibits microtubule depolymerization and is active against multidrug-resistant cancer cell lines and paclitaxel-resistant tumors. The most comprehensively characterized and so far only epothilone derivative, which received FDA approval for clinical use, is ixabepi-lone. The compound is marketed in the US by Bristol-Myers Squibb (BMS) under the trade name Ixembra . 

Docetaxel is the second representative of the new entity of drugs that have a unique taxane ring in common, such as the one seen in pachtaxel. Being more efficacious than paclitaxel, docetaxel is used in ovarian cancer. Paclitaxel and docetaxel inhibit microtubule depolymerization, thereby reducing the formation of stable microtubule bundles (see also Figure 15). 

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