Microtubule dynamic instability

Panda D, Rathinasamy K, Santra MK, Wilson L (2005) Kinetic Suppression of Microtubule Dynamic Instability by Griseofiilvin Implications for its Possible Use in the Treatment of Cancer. Proc Natl Acad Sci USA 102 9878... 

Erickson HP, O Brien ET. Microtubule dynamic instability and GTP hydrolysis. Annu. Rev. Biophys. Biomol. Struct. 1992 21 145-166. 

Bayley PM, Martin Sr, Microtubule dynamic instability some possible physical mechanisms and their implications. Biochem. Soc. Trans. 1991 19 1023-1028. 

Tran PT, Walker RA, Salmon ED. A metastable intermediate state of microtubule dynamic instability that differs significantly between plus and minus ends. J. CeU. Biol. 1997 138 105-117. 

Anticancer taxanes initially were isolated from the bark of the Pacific yew Taxus brevifolia) but are now produced semisynthetically from an inactive natural precursor found in the leaves of the European yew (Taxus baccata) a renewable resource. Taxanes bind to polymerized (elongated) (3-tubulin at a specific receptor site located within the tubular lumen. At standard therapeutic doses (which should lead to intracellular concentrations of 1-20 pM), taxane-tubulin binding renders the microtubules resistant to depolymerization and prone to polymerization (69). This promotes the elongation phase of microtubule dynamic instability at the expense of the shortening phase, and it inhibits the disassembly of the tubule into the mitotic spindle. In turn, this interrupts the normal process of cell division. At these concentrations, extensive polymerization causes the formation of large and ... 

Howell, B., Odde, D.J., and Cassimeris, L., Kinase and phosphatase inhibitors cause rapid alterations in microtubule dynamic instability in living cells. Cell Motyl. Cytoskel, 38, 201, 1997. 

Fresh human blood mononuclear cells contained an average of 26 microtubules per cell which significantly increased to 31 microtubules per cell following a 30-min exposure to LPS P <0.001). Using a nocodazole-based assay of microtubule dynamic instability, the half-life of fresh unstimulated monocyte microtubules was approximately 18 s and extended to 26 s following a 30-min exposure to LPS (Allen et al. 1997). Endotoxin caused a rapid alteration in monocyte microtubule stability (Allen et al. 1997). 

Newport-. The way that spindles and microtubules are normally reoriented is by the stabilization of dynamic instability at the plus-end of the microtubule. So if microtubules were to embed in this apically localized complex, they would effectively be capped and this would reorient the spindle. One would expect that this would happen to the centriole prior to mitosis, so that the interphase microtubules would be stabilized at that location as well. Are you saying this doesn t happen If it doesn t happen, perhaps Cdc2 is necessary to activate this apical region for stabilizing plus ends, and this would explain why it rocks about. Are any of these molecules potential candidates for capping microtubules at the plus-end, for instance ... 

Like microfilaments, microtubules are dynamic structures with (+) and (-) ends. The (-) end is usually stabilized by bonding to the centrosome. The (+) end shows dynamic instability, it can either grow slowly or shorten rapidly. GTR which is bound by the microtubules and gradually hydrolyzed into GDR plays a role in this. Various proteins can also be associated with microtubules. 

DYNAMIC INSTABILITY DEPOLYMERIZATION, END-WISE MICROTUBULE TREADMILLING POLYMERIZATION RANDOM SCISSION KINETICS DEPOLYMERIZATION, END-WISE Deracemization,... 

Dynamic instability of microtubules, MICROTUBULE ASSEMBLY KINETICS Dynamic light scattering,... 

These proteins form complexes with cdc20, thereby sequestering it from activating the APC/C complex (66) (Fig. 4). The spindle checkpoint is activated in response to various spindle poisons, such as nocodazole, a drug that depolymerizes microtubules and thus prevents the attachment of microtubules to the kinetochores. On the other hand, taxanes inhibit the dynamic instability of the spindle and allow microtubule attachment but prevent the generation of tension across kinetochores. 

In order to understand the logic of dynamic instability, we need to keep in mind that cytoskeletal filaments are unstable only when their ends are not attached to particular molecules that have the ability to anchor them. Every microtubule, for example, starts from an organising centre (the centrosome), and the extremity which is attached to this structure is perfectly stable, whereas the other extremity can grow longer or shorter, and becomes stable only when it encounters an anchoring molecule in the cytoplasm. If such an anchor is not found, the whole microtubule is rapidly dismantled and another is launched in another direction, thus allowing the cytoskeleton to explore all the cytoplasm s space in a short time. 

A classic example of this strategy is offered by mitosis. In this case it is imperative that microtubules become attached to the centromeres, so that the chromosomes can be transported to opposite ends of the splindle, but centromes are extremely small and their distribution in space is virtually random. Looking for centromeres is literally like looking for a needle in a haystack, and yet the exploratory mechanism of dynamic instability always finds them, and always manages to find... 

We conclude that dynamic instability is a means of creating an endless stream of cell types with only one common structure and with the choice of a few anchoring molecules. But this is possible only because there is no necessary relationship between the common structure of the cytoskeleton and the cellular structures that the cytoskeleton is working on. The anchoring molecules (or accessory proteins) are true adaptors that perform two independent recognition processes microtubules on one side and different cellular structures on the other side. The resulting correspondence is based therefore on arbitrary rules, on true natural conventions that we can refer to as the cytoskeleton codes. 

At steady state, a pool of free heterodimers (representing the critical concentration) coexists with filaments. For these filaments, the critical concentration is lower at the plus end than at the minus end. Thus, treadmilling can occur with a net loss of protomers from the minus end and net addition at the plus end. However, for microtubules, treadmilling is generally overshadowed by a related and much more dramatic phenomenon known as dynamic instability. If a filament loses its GTP cap at either end, depolymerization at that end occurs extremely rapidly. Thus, even at steady state, some filaments can be rapidly shortening at one or both ends while other filaments are rapidly growing at one or both ends. Dynamic instability also occurs in vivo and is an essential factor in the proper functioning of many microtubule-based networks. 

Three types of microtubule can readily be defined in the mitotic spindle. Polar microtubules overlap (and probably interact) between the poles and are involved in pushing the poles apart in anaphase. Astral microtubules radiate in all directions and also help separate the poles. Kinetochore microtubules attach themselves to specialized protein structures (kinetochores) located on each side of the centromere of each chromosome. These microtubules are involved in moving the chromosomes to the metaphase plate and in separating sister chromatids at anaphase. The microtubules in the spindle are very dynamic and have a half-life of only a few seconds. This appears to be especially important in the capture of chromosomes by the kinetochore microtubules. Microtubules that miss the target kinetochores are quickly lost because their dynamic instability soon leads to depolymerization. The new microtubules that form may hit the target and be partially stabilized through plus-end capping. 

The spindle contains a number of dynein- and kinesin-family motors (Fig. 5-37). These, together with the dynamic instability and treadmilling of the microtubules, help control the movement and relative positions of the chromosomes and the poles. The spindle is under constant tension resulting from a range of forces. 

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