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microtubules

Wednesday 17 September 2003

Definition: Microtubules is a cytoskeletal component composed of filamentous polymers of tubulin. Microtubules are involved in many cellular functions including axonal transport, structural integrity and motility.

Microtubules are essential and ubiquitous elements of the cytoskeleton. Their filamentous arrays contribute to an impressive diversity of biologic functions that include cell division, intracellular transport, and the maintenance of cellular architecture. The subunit from which microtubules are assembled is the tubulin heterodimer, which consists of 1 alpha-tubulin and 1 beta-tubulin polypeptide, each of about 50 kD.

Microtubules are essential for various cellular processes including cell division and intracellular organization. Their function depends on their ability to rearrange their distribution at different times and places. Microtubules are dynamic polymers and their behaviour is described as dynamic instability.

The microtubule array has a central role in the regulation of cell shape and polarity during differentiation, chromosome partitioning at mitosis, and intracellular transport. Microtubules undergo rearrangements involving rapid transitions between stable and dynamic states during these processes.

Microtubules mediate adaptation and maintenance of the cytoskeleton. The polymerization and depolymerization of alpha-tubulins (MIM.602529) and beta-tubulins (MIM.191130) controls the assembly and disassembly of microtubules.

Microtubules-associated proteins or MAPs (MIM.600178), regulate the dynamics and stability of microtubules, and different types of MTs contain different MAPs.

Microtubule tips

Microtubule plus-end tracking proteins (+TIPs) are a diverse group of evolutionarily conserved cellular factors that accumulate at the ends of growing microtubules. They form dynamic networks through the interaction of a limited set of protein modules, repeat sequences and linear motifs that bind to each other with moderate affinities. +TIPs regulate different aspects of cell architecture by controlling microtubule dynamics, microtubule interactions with cellular structures and signalling factors, and the forces that are exerted on microtubule networks.

Pathology of microtubules

- anomalies of microtubules stability

  • anomalies of the protein tau (taupathies)

- cellular cilia dysfunctions

-  pathology of MAPs (microtubule-associated proteins)

  • taupathies - pathology of the microtubule-associated protein tau (TAU)

- pathology of tubulins
- pathology of tubulin-specific chaperones

Therapeutics

Targeting microtubules for cancerchemotherapy. Chemical compounds that interfere with microtubules such as the vinca alkaloids and taxanes are important chemotherapeutic agents for the treatment of cancer.

As our knowledge of microtubule-targeting drugs increases, we realize that the mechanism underlying the anti-cancer activity of these agents may mainly lie in their inhibitory effects on spindle microtubule dynamics, rather than in their effects on microtubule polymer mass.

There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell cycle progression at mitosis and eventually leading to apoptotic cell death. The effectiveness of microtubule-targeting drugs for cancer therapy has been impaired by various side effects, notably neurological and hematological toxicities.

Drug resistance is another notorious factor that thwarts the effectiveness of these agents, as with many other cancer chemotherapeutics. Several new microtubule-targeting agents have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to the existing microtubule-targeting drugs.

See also:

- microtubules stability
- microtubule-associated proteins (MAPs)

  • tau protein (TAU)

- MARKs

References

- Akhmanova A, Steinmetz MO. Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nat Rev Mol Cell Biol. 2008 Apr;9(4):309-22. PMID: 18322465

- Luders J, Stearns T. Microtubule-organizing centres: a re-evaluation. Nat Rev Mol Cell Biol. 2007 Feb;8(2):161-7. PMID: 17245416

- Keller CE, Lauring BP. Possible regulation of microtubules through destabilization of tubulin. Trends Cell Biol. 2005 Nov;15(11):571-3. Epub 2005 Oct 3. PMID: 16202601

- Baas PW, Karabay A, Qiang L. Microtubules cut and run. Trends Cell Biol. 2005 Oct;15(10):518-24. PMID: 16126385

- Baas PW, Qiang L. Neuronal microtubules: when the MAP is the roadblock. Trends Cell Biol. 2005 Apr;15(4):183-7. PMID: 15817373

- Guzik BW, Goldstein LS. Microtubule-dependent transport in neurons: steps towards an understanding of regulation, function and dysfunction. Curr Opin Cell Biol. 2004 Aug;16(4):443-50. PMID: 15261678

- Zheng Y. G protein control of microtubule assembly. Annu Rev Cell Dev Biol. 2004;20:867-94. PMID: 15473863

- Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004 Apr;4(4):253-65. PMID: 15057285

- Carvalho P, Tirnauer JS, Pellman D. Surfing on microtubule ends. Trends Cell Biol. 2003 May;13(5):229-37. PMID: 12742166

- Maly IV, Borisy GG. Self-organization of treadmilling microtubules into a polar array. Trends Cell Biol. 2002 Oct ;12(10):462-5. PMID : 12441249

- Kinoshita K, Habermann B, Hyman AA. XMAP215: a key component of the dynamic microtubule cytoskeleton. Trends Cell Biol. 2002 Jun;12(6):267-73. PMID: 12074886

- Oakley BR. An abundance of tubulins. Trends Cell Biol. 2000 Dec;10(12):537-42. PMID: 11121746

- Andersen SS. Spindle assembly and the art of regulating microtubule dynamics by MAPs and Stathmin/Op18. Trends Cell Biol. 2000 Jul;10(7):261-7.
PMID: 10856928


- Build a mictotubule at Structural Biochemistry Group, University of Edinburgh, UK