Cold-induced microtubule depolymerization

The generality of the end-wise depolymerization kinetic model is indicated by the comparison of the observed and predicted time-courses of cold-induced microtubule disassembly (Fig. 3). See Self-Assembly Protein Polymerization... 

Figure 3. Progress curve for cold-induced depolymerization after chilling microtubules (assembled at 30°C using 2.1 mg/ml tubulin and 0.4 mg/ml microtubule-associated proteins). The data points are experimentally determined, and the solid line is based on the theoretical treatment -T...

The basic biology and pharmacology of Epo B (as the most potent and most widely studied natural epothilone) have been summarized in several previous review articles.As indicated in Section 1.1, the biological effects of the compound are based on its ability to bind to microtubules and alter the intrinsic stabihty and dynamic properties of these supramolecular structures. In cell-free in vitro systems, this is demonstrated by the prevention of Ca - or cold-induced depolymerization of preformed microtubule polymers as well as by the promotion of tubuhn polymerization (to form microtubule-like polymers) in the absence of either microtubule-associated proteins (MAPs) and/or guanosine triphosphate (GTP), at temperatures significantly below 37 °C, and in the presence of The latter... 

In line with its effects on mbulin polymerization in vitro (i.e., in an excellular context), the prevention of cold-induced depolymerization of micrombules by epothilones has also been demonstrated in cells. Microtubule stabilization in intact cells (as well as cancer cell growth inhibition, vide infra), however, is observed at strikingly lower concentrations than those required for the induction... 

As indicated above, the antitumor activity of Epo B is based on its ability to bind to microtubules and to alter their intrinsic stability and dynamic properties. (For excellent reviews on microtubule structure and function see ref. 6 and 47-49.) Epothilones prevent the Ca or cold-induced depolymerization of pre-existing microtubule polymers in cell-free systems at the same time, they promote the polymerization of soluble tubulin into microtubule-like polymers under conditions that would normally destabilize microtubules.As demonstrated by kinetic experiments, epothilones inhibit the binding of taxol to microtubules in a competitive manner and they bind to the taxol binding site on p-tubulin with affinities that exceed (Epo B) or are comparable (Epo A) to taxol affinity likewise Epo B is a more potent tubulin-polymerizing agent than taxol or Epo Structural studies on... 

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