Tubulin modifications and their cellular functions

Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Current Opinion in Cell Biology (Impact Factor: 8.47). 03/2008; 20(1):71-6. DOI: 10.1016/
Source: PubMed


All microtubules are built from a basic alpha/beta-tubulin building block, yet subpopulations of microtubules can be differentially marked by a number of post-translational modifications. These modifications, conserved throughout evolution, are thought to act individually or in combination to control specific microtubule-based functions, analogous to how histone modifications regulate chromatin functions. Here we review recent studies demonstrating that tubulin modifications influence microtubule-associated proteins such as severing proteins, plus-end tracking proteins, and molecular motors. In this way, tubulin modifications play an important role in regulating microtubule properties, such as stability and structure, as well as microtubule-based functions, such as ciliary beating, cell division, and intracellular trafficking.

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    • "It is well known that the basic resistance mechanism of fungal species to fungicides is due to a modification at the target-site of fungicidal action (Brent and Hollomon 1998). The interrelationships of carbendazim resistance with point mutations of the β-tubulin gene have been analyzed in details (Verhey and Gaetig 2007; Hammond et al. 2008; Cheng et al. 2009). Many studies have shown that the mechanism of action for carbendazim fungicides is binding to β-tubulin and preventing α-tubulin assembly (Fujimura et al. 1992; Cools et al. 2011; Cools and Fraaije 2012). "
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    ABSTRACT: The application of fungicides is so critical, especially in greenhouses, to avoid fungal infections. Carbendazim, an inhibitor of tubulin biosynthesis, is the most widely known broad-spectrum benzimidazole fungicide. The application of carbendazim affects other beneficial fungi as well. Paecilomyces lilacinus 36-1 (Pl36-1) is a beneficial fungus used for biological control, and the most effective biocontrol agents of nematode eggs. The Pl36-1 is sensitive to carbendazim (0.3 μg/ml). There is a general consensus that the mechanisms of resistance to carbendazim in the β-tubulin gene have been analyzed in detail. However, no studies were conducted on P. lilacinus strains. In the present study, two carbendazim-resistant mutants of Pl36-1, P50 and P100, were obtained from UV exposure and tested. The β-tubulin gene fragments were cloned and sequenced in the three strains, Pl36-1, P50 and P100. The resistance to carbendazim was developed when amino acid substitutions occurred at β-tubulin gene positions of S145A, T185A and F200Y. The β-tubulin gene was overexpressed in Pl36-1 strains. The β-tubulin expression level of the overexpressed mutant (PL3), quantified by qRT-PCR, was increased 4-folds over its normal level in Pl36-1. In vitro, the PL3 was resistant to carbendazim with maintaining growth, sporulation and pathogenicity rates. Three-year field trial demonstrated that P100 and PL3 strains exhibited carbendazim resistance combined with high nematode reduction and yield improvement.
    European Journal of Plant Pathology 05/2015; 143(1):57-68. DOI:10.1007/s10658-015-0665-0 · 1.49 Impact Factor
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    • "Similarly to the actin filaments, microtubules play a critical role in cell stability and dynamics. Proper regulation of microtubule components relies on post translational modifications such as a-tubulin acetylation (Hammond et al., 2008). Microtubule deacetylation is carried out by histone deacetylase (HDAC) 6, a class II HDAC and the class III HDAC sirtuin 2 (SIRT2), which form a complex that allows them to bind to tubulin (Hubbert et al., 2002; Nahhas et al., 2007; Sadoul et al., 2011; Yang and Seto, 2008). "
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    ABSTRACT: Methamphetamine (METH) is a powerful psychostimulant drug used worldwide for its reinforcing properties. In addition to the classic long-lasting monoaminergic-disrupting effects extensively described in the literature, METH has been consistently reported to increase blood brain barrier (BBB) permeability, both in vivo and in vitro, as a result of tight junction and cytoskeleton disarrangement. Microtubules play a critical role in cell stability, which relies on post-translational modifications such as α-tubulin acetylation. As there is evidence that psychostimulants drugs modulate the expression of histone deacetylases (HDACs), we hypothesized that in endothelial cells METH-mediation of cytoplasmatic HDAC6 activity could affect tubulin acetylation and further contribute to BBB dysfunction. To validate our hypothesis, we exposed the bEnd.3 endothelial cells to increasing doses of METH and verified that it leads to an extensive α-tubulin deacetylation mediated by HDACs activation. Furthermore, since we recently reported that acetyl-l-carnitine (ALC), a natural occurring compound, prevents BBB structural loss in a context of METH exposure, we reasoned that ALC could also preserve the acetylation of microtubules under METH action. The present results confirm that ALC is able to prevent METH-induced deacetylation providing effective protection on microtubule acetylation. Although further investigation is still needed, HDACs regulation may become a new therapeutic target for ALC. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Toxicology Letters 02/2015; 234(2). DOI:10.1016/j.toxlet.2015.02.011 · 3.26 Impact Factor
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    • "Once ligand-bound, AR uses the microtubule network in prostate cancer cells to translocate into the nucleus [60] [61]. Acetylation of the α-tubulin subunits normally plays a role in intracellular trafficking of proteins by increasing dynein binding affinity for it, enabling AR nuclear translocation [59]. During prostate tumorigenesis tubulin acetylation increases cancer cell motility and invasion [62]. "
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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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