Regulation of microtubule dynamic instability

Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
Biochemical Society Transactions (Impact Factor: 3.19). 10/2009; 37(Pt 5):1007-13. DOI: 10.1042/BST0371007
Source: PubMed


Proper regulation of MT (microtubule) dynamics is essential for various vital processes, including the segregation of chromosomes, directional cell migration and differentiation. MT assembly and disassembly is modulated by a complex network of intracellular factors that co-operate or antagonize each other, are highly regulated in space and time and are thus attuned to the cell cycle and differentiation processes. While we only begin to appreciate how the concerted action of MT stabilizers and destabilizers shapes different MT patterns, a clear picture of how individual factors affect the MT structure is emerging. In this paper, we review the current knowledge about proteins that modulate MT dynamic instability.

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Available from: Anne Straube, Oct 06, 2015
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    • "Other microtubule disassembly proteins exist in a cell beyond the kinesin-13 family. The kinesin-8 family of proteins also participates in length dependent depolymerization of microtubules by binding to the growing end and accumulating there [50]. These particular microtubule binding proteins are imperative to alignment of chromosomes at the equator of the cell during mitosis. "
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    ABSTRACT: Prostate cancer is a disease that affects hundreds of thousands of men in the United States each year. In the early stages of advanced prostate cancer, the disease can be suppressed by androgen deprivation therapy (ADT). Eventually, however, most patients experience resistance to androgen deprivation, and their treatment transitions to alternative targeting of the androgen axis with abiraterone and enzalutamide, as well as taxane-based chemotherapy. Development of advanced castration-resistant prostate cancer (CRPC) is a consequence of lack of an apoptotic response by the tumor cells to treatment. Understanding the mechanisms contributing to prostate tumor therapeutic resistance and progression to metastasis requires dissection of the signaling mechanisms navigating tumor invasion and metastasis as mediated by cell-matrix interactions engaging components of the extracellular matrix (ECM), to form adhesion complexes. For a tumor call to metastasize from the primary tumor, it requires disruption of cell-cell interactions from the surrounding cells, as well as detachment from the ECM and resistance to anoikis (apoptosis upon cell detachment from ECM). Attachment, movement and invasion of cancer cells are functionally facilitated by the actin cytoskeleton and tubulin as the structural component of microtubules. Transforming growth factor (TGF)-β has tumor-inhibitory activity in the early stages of tumorigenesis, but it promotes tumor invasive characteristics in metastatic disease. Recent evidence implicates active (dephosphorylated) cofilin, an F-actin severing protein required for cytoskeleton reorganization, as an important contributor to switching TGF-β characteristics from a growth suppressor to a promoter of prostate cancer invasion and metastasis. Cancer cells eventually lose the ability to adhere to adjacent neighboring cells as well as ECM proteins, and via epithelial-mesenchymal transition (EMT), acquire invasive and metastatic characteristics. Microtubule-targeting chemotherapeutic agents, taxanes, are used in combination with antiandrogen strategies to increase the survival rate in patients with CRPC. This review addresses the development of therapeutic platform for targeting the integrity of actin cytoskeleton to impair prostate cancer progression.
    11/2014; 2(1):15-26.
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    • "At lower concentrations, where no macroscopic effect can be seen on microtubule network, these drugs are known to have an effect on microtubule dynamics which can be monitored by time-lapse video microscopy. Following the ends of individual microtubules at the cell periphery (Fig. 4c) enables one to obtain a great number of dynamicity parameters that characterize subtle effects of drugs, such as speed of growth, depolymerization, time spent in pause, frequency of transition from growth to depolymerization (catastrophe) or the opposite (rescue) (Gardner et al. 2012; Kirschner and Mitchison 1986; van der Vaart et al. 2009). This approach lead to the discovery that, although having opposite effect on the microtubule formation at high concentrations (stabilization or destabilization), the three leading compounds , paclitaxel, vinblastine and colchicine and their analogs usually perturb MT functions by decreasing microtubules dynamics instability (Jordan and Wilson 1998). "
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    ABSTRACT: Even though commercialized anticancer drugs are now produced by pharmaceutical companies, most of them were originally obtained from natural sources, and more particularly from plants. Indeed, many structurally diverse compounds isolated from plants or marine flora have been purified and synthesized for their anticancer bioactivity. Among these, several molecules belong to the class of anticancer drugs which target the microtubule cytoskeleton, either by stabilizing it or destabilizing it. To characterize the activity of these drugs and to understand in which physiological context they are more likely to be used as therapeutic agents, it is necessary to fully determine their interaction with tubulin. Understanding the molecular basis of their effects on microtubule cytoskeleton is an important step in designing analogs with greater pharmacological activity and with fewer side effects. In addition, knowing the molecular mechanism of action of each drug that is already used in chemotherapy protocols will also help to find strategies to circumvent resistance. By taking examples of known anti-tubulin plant derived drugs, we show how identification of microtubule targeting agents and further characterization of their activity can be achieved combining biophysical and biochemical approaches. We also illustrate how continuing in depth study of molecules with already known primary mechanisms of action can lead to the discovery of new targets or biomarkers which can open new perspectives in anticancer strategies.
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    • "MTs undergo rapid cycles of polymerization and depolymerization (dynamic instability): this behaviour is regulated by GTP binding and hydrolysis [Howard and Hyman, 2009; Wade, 2009]. This inherent (dynamic) instability of MTs is carefully regulated by the cell (regulatory mechanisms include posttranslational modifications of the tubulin dimer, and the binding of MAPs) for specific functional purposes [Etienne-Manneville, 2010; van der Vaart et al., 2009]. "
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    Cytoskeleton 10/2013; 70(10). DOI:10.1002/cm.21118 · 3.12 Impact Factor
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