Special Issue "Tubulin: Structure, Functions and Roles in Disease"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Motility and Adhesion".

Deadline for manuscript submissions: closed (28 February 2019).

Special Issue Editors

Dr. Pavla Binarová
Website
Guest Editor
Academy of Sciences of the Czech Republic, Prague, Czech Republic
Interests: molecular and cell biology of microtubular cytoskeleton; gamma-tubulin and its role in microtubule nucleation and organization; gamma-tubulin as filament forming tubulin and its scaffolding and sequestration role in nuclear processes
Prof. Dr. Jack A. Tuszynski
Website
Guest Editor
Department of Oncology, University of Alberta, AB T6G 1Z2 Edmonton, Canada
Interests: computational drug design; systems biology of cancer and neurodegenerative diseases; tubulin
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Microtubules are assembled from highly conserved α and β-tubulin dimers and perform multiple cellular functions in intracellular transport, in determining cell shape and polarity and in the cell division. Microtubules are essential also for assembly of specialized structures of cilia, flagella or centrioles. Tubulin exists in forms of different isotypes with spatially and temporally regulated expression and some isotypes are differentially expressed in normal and neoplastic cells. For example, tubulin βIII isotype is overexpressed in many metastatic cancers and serves as a prognostic marker in certain types of cancer. Understanding mutations in isotypes of tubulin expressed in invasive tumors and differing in binding of anti-cancer drugs will help to uncover potentially relevant molecular targets for design of novel drugs. Moreover, α/β-tubulins are altered by posttranslational modifications which change microtubule behavior also through modification of interaction with microtubule associated proteins including motors and effectors of microtubule dynamics. Understanding of usage of tubulin isotypes and posttranslational modifications in physiological and pathological conditions will help to uncover role of tubulins in regulation of cell division, in centrosomal functions and in processes, such as ciliogenesis or neuronal differentiation. This Special Issue of Cells should improve our understanding of a link of tubulin code which programs microtubules for specific functions with human pathologies. There is a growing number of bacterial tubulins that evolved wide range of cytoskeletal functions. Ability to assemble protofilaments and fibrilar structures characteristics of prokaryotic tubulins is preserved for γ-tubulin a conserved member of eukaryotic tubulin superfamily specialized for microtubule nucleation and with much less understood functions in nuclear and cell cycle related processes. Characterization of tubulins which are on an evolutionary cusp between prokaryotes and eukaryotes will also help our understanding how structure of tubulins is related to their multiple cellular functions under normal and pathological conditions.

Dr. Pavla Binarová
Prof. Jack Tusczynski
Guest Editors

Manuscript Submission Information

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Keywords

  • tubulins
  • structure and functions
  • posttranslational modifications
  • physiological roles and pathologies

Published Papers (9 papers)

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Editorial

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Open AccessEditorial
Tubulin: Structure, Functions and Roles in Disease
Cells 2019, 8(10), 1294; https://doi.org/10.3390/cells8101294 - 22 Oct 2019
Cited by 1
Abstract
Highly conserved α- and β-tubulin heterodimers assemble into dynamic microtubules and perform multiple important cellular functions such as structural support, pathway for transport and force generation in cell division. Tubulin exists in different forms of isotypes expressed by specific genes with spatially- and [...] Read more.
Highly conserved α- and β-tubulin heterodimers assemble into dynamic microtubules and perform multiple important cellular functions such as structural support, pathway for transport and force generation in cell division. Tubulin exists in different forms of isotypes expressed by specific genes with spatially- and temporally-regulated expression levels. Some tubulin isotypes are differentially expressed in normal and neoplastic cells, providing a basis for cancer chemotherapy drug development. Moreover, specific tubulin isotypes are overexpressed and localized in the nuclei of cancer cells and/or show bioenergetic functions through the regulation of the permeability of mitochondrial ion channels. It has also become clear that tubulin isotypes are involved in multiple cellular functions without being incorporated into microtubule structures. Understanding the mutations of tubulin isotypes specifically expressed in tumors and their post-translational modifications might help to identify precise molecular targets for the design of novel anti-microtubular drugs. Knowledge of tubulin mutations present in tubulinopathies brings into focus cellular functions of tubulin in brain pathologies such as Alzheimer’s disease. Uncovering signaling pathways which affect tubulin functions during antigen-mediated activation of mast cells presents a major challenge in developing new strategies for the treatment of inflammatory and allergic diseases. γ-tubulin, a conserved member of the eukaryotic tubulin superfamily specialized for microtubule nucleation is a target of cell cycle and stress signaling. Besides its microtubule nucleation role, γ-tubulin functions in nuclear and cell cycle related processes. This special issue “Tubulin: Structure, Functions and Roles in Disease” contains eight articles, five of which are original research papers and three are review papers that cover diverse areas of tubulin biology and functions under normal and pathological conditions. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)

Research

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Open AccessArticle
Epilepsy in Tubulinopathy: Personal Series and Literature Review
Cells 2019, 8(7), 669; https://doi.org/10.3390/cells8070669 - 02 Jul 2019
Cited by 6
Abstract
Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation and axon guidance and maintenance. Motor impairment, intellectual disability and epilepsy are the main clinical symptoms. In the present study 15 patients from [...] Read more.
Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation and axon guidance and maintenance. Motor impairment, intellectual disability and epilepsy are the main clinical symptoms. In the present study 15 patients from a personal cohort and 75 from 21 published studies carrying mutations in TUBA1A, TUBB2B and TUBB3 tubulin genes were evaluated with the aim to define a clinical and electrophysiological associated pattern. Epilepsy shows a wide range of severity without a specific pattern. Mutations in TUBA1A (60%) and TUBB2B (74%) and TUBB3 (25%) genes are associated with epilepsy. The accurate analysis of the Electroencephalogram (EEG) pattern in wakefulness and sleep in our series allows us to detect significant abnormalities of the background activity in 100% of patients. The involvement of white matter and of the inter-hemispheric connection structures typically observed in tubulinopathies is evidenced by the high percentage of asynchronisms in the organization of sleep activity recorded. In addition to asymmetries of the background activity, excess of slowing, low amplitude and Magnetic Resonance (MR) imaging confirm the presence of extensive brain malformations involving subcortical and midline structures. In conclusion, epilepsy in tubulinopathies when present has a favorable evolution over time suggesting a not particularly aggressive therapeutic approach. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Open AccessFeature PaperArticle
Regulation of Microtubule Nucleation in Mouse Bone Marrow-Derived Mast Cells by Protein Tyrosine Phosphatase SHP-1
Cells 2019, 8(4), 345; https://doi.org/10.3390/cells8040345 - 11 Apr 2019
Cited by 3
Abstract
The antigen-mediated activation of mast cells initiates signaling events leading to their degranulation, to the release of inflammatory mediators, and to the synthesis of cytokines and chemokines. Although rapid and transient microtubule reorganization during activation has been described, the molecular mechanisms that control [...] Read more.
The antigen-mediated activation of mast cells initiates signaling events leading to their degranulation, to the release of inflammatory mediators, and to the synthesis of cytokines and chemokines. Although rapid and transient microtubule reorganization during activation has been described, the molecular mechanisms that control their rearrangement are largely unknown. Microtubule nucleation is mediated by γ-tubulin complexes. In this study, we report on the regulation of microtubule nucleation in bone marrow-derived mast cells (BMMCs) by Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1; Ptpn6). Reciprocal immunoprecipitation experiments and pull-down assays revealed that SHP-1 is present in complexes containing γ-tubulin complex proteins and protein tyrosine kinase Syk. Microtubule regrowth experiments in cells with deleted SHP-1 showed a stimulation of microtubule nucleation, and phenotypic rescue experiments confirmed that SHP-1 represents a negative regulator of microtubule nucleation in BMMCs. Moreover, the inhibition of the SHP-1 activity by inhibitors TPI-1 and NSC87877 also augmented microtubule nucleation. The regulation was due to changes in γ-tubulin accumulation. Further experiments with antigen-activated cells showed that the deletion of SHP-1 stimulated the generation of microtubule protrusions, the activity of Syk kinase, and degranulation. Our data suggest a novel mechanism for the suppression of microtubule formation in the later stages of mast cell activation. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Open AccessArticle
Over-Expression of βII-Tubulin and Especially Its Localization in Cell Nuclei Correlates with Poorer Outcomes in Colorectal Cancer
Cells 2019, 8(1), 25; https://doi.org/10.3390/cells8010025 - 07 Jan 2019
Cited by 5
Abstract
Tubulin is a heterodimer of α and β subunits, both existing as isotypes differing in amino acid sequence encoded by different genes. Specific isotypes of tubulin have associations with cancer that are not well understood. Previous studies found that βII-tubulin is expressed in [...] Read more.
Tubulin is a heterodimer of α and β subunits, both existing as isotypes differing in amino acid sequence encoded by different genes. Specific isotypes of tubulin have associations with cancer that are not well understood. Previous studies found that βII-tubulin is expressed in a number of transformed cells and that this isotype is found in cell nuclei in non-microtubule form. The association of βII expression and its nuclear localization with cancer progression has not previously been addressed. We here used a monoclonal antibody to βII to examine patients with colorectal cancer and found that patients whose tumors over-express βII have a greatly decreased life expectancy which is even shorter in those patients with nuclear βII. Our results suggest that βII-tubulin may facilitate cancer growth and metastasis and, to accomplish this, may not need to be in microtubule form. Furthermore, βII expression and localization could be a useful prognostic marker. We also found that βII appears in the nuclei of otherwise normal cells adjacent to the tumor. It is possible therefore that cancer cells expressing βII influence nearby cells to do the same and to localize βII in their nuclei by an as yet uncharacterized regulatory pathway. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Open AccessFeature PaperArticle
Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents
Cells 2018, 7(11), 216; https://doi.org/10.3390/cells7110216 - 19 Nov 2018
Cited by 9
Abstract
Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series [...] Read more.
Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Open AccessFeature PaperArticle
Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives
Cells 2018, 7(11), 192; https://doi.org/10.3390/cells7110192 - 01 Nov 2018
Cited by 11
Abstract
Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer [...] Read more.
Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Review

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Open AccessReview
Regulating the BCL2 Family to Improve Sensitivity to Microtubule Targeting Agents
Cells 2019, 8(4), 346; https://doi.org/10.3390/cells8040346 - 12 Apr 2019
Cited by 12
Abstract
Chemotherapeutic targeting of microtubules has been the standard of care in treating a variety of malignancies for decades. During mitosis, increased microtubule dynamics are necessary for mitotic spindle formation and successful chromosomal segregation. Microtubule targeting agents (MTAs) disrupt the dynamics necessary for successful [...] Read more.
Chemotherapeutic targeting of microtubules has been the standard of care in treating a variety of malignancies for decades. During mitosis, increased microtubule dynamics are necessary for mitotic spindle formation and successful chromosomal segregation. Microtubule targeting agents (MTAs) disrupt the dynamics necessary for successful spindle assembly and trigger programmed cell death (apoptosis). As the critical regulators of apoptosis, anti-apoptotic BCL2 family members are often amplified during carcinogenesis that can result in MTA resistance. This review outlines how BCL2 family regulation is positioned within the context of MTA treatment and explores the potential of combination therapy of MTAs with emerging BCL2 family inhibitors. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Open AccessFeature PaperReview
Microtubular and Nuclear Functions of γ-Tubulin: Are They LINCed?
Cells 2019, 8(3), 259; https://doi.org/10.3390/cells8030259 - 19 Mar 2019
Cited by 7
Abstract
γ-Tubulin is a conserved member of the tubulin superfamily with a function in microtubule nucleation. Proteins of γ-tubulin complexes serve as nucleation templates as well as a majority of other proteins contributing to centrosomal and non-centrosomal nucleation, conserved across eukaryotes. There is a [...] Read more.
γ-Tubulin is a conserved member of the tubulin superfamily with a function in microtubule nucleation. Proteins of γ-tubulin complexes serve as nucleation templates as well as a majority of other proteins contributing to centrosomal and non-centrosomal nucleation, conserved across eukaryotes. There is a growing amount of evidence of γ-tubulin functions besides microtubule nucleation in transcription, DNA damage response, chromatin remodeling, and on its interactions with tumor suppressors. However, the molecular mechanisms are not well understood. Furthermore, interactions with lamin and SUN proteins of the LINC complex suggest the role of γ-tubulin in the coupling of nuclear organization with cytoskeletons. γ-Tubulin that belongs to the clade of eukaryotic tubulins shows characteristics of both prokaryotic and eukaryotic tubulins. Both human and plant γ-tubulins preserve the ability of prokaryotic tubulins to assemble filaments and higher-order fibrillar networks. γ-Tubulin filaments, with bundling and aggregating capacity, are suggested to perform complex scaffolding and sequestration functions. In this review, we discuss a plethora of γ-tubulin molecular interactions and cellular functions, as well as recent advances in understanding the molecular mechanisms behind them. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Open AccessReview
Tubulin βII and βIII Isoforms as the Regulators of VDAC Channel Permeability in Health and Disease
Cells 2019, 8(3), 239; https://doi.org/10.3390/cells8030239 - 13 Mar 2019
Cited by 14
Abstract
In recent decades, there have been several models describing the relationships between the cytoskeleton and the bioenergetic function of the cell. The main player in these models is the voltage-dependent anion channel (VDAC), located in the mitochondrial outer membrane. Most metabolites including respiratory [...] Read more.
In recent decades, there have been several models describing the relationships between the cytoskeleton and the bioenergetic function of the cell. The main player in these models is the voltage-dependent anion channel (VDAC), located in the mitochondrial outer membrane. Most metabolites including respiratory substrates, ADP, and Pi enter mitochondria only through VDAC. At the same time, high-energy phosphates are channeled out and directed to cellular energy transfer networks. Regulation of these energy fluxes is controlled by β-tubulin, bound to VDAC. It is also thought that β-tubulin‒VDAC interaction modulates cellular energy metabolism in cancer, e.g., switching from oxidative phosphorylation to glycolysis. In this review we focus on the described roles of unpolymerized αβ-tubulin heterodimers in regulating VDAC permeability for adenine nucleotides and cellular bioenergetics. We introduce the Mitochondrial Interactosome model and the function of the βII-tubulin subunit in this model in muscle cells and brain synaptosomes, and also consider the role of βIII-tubulin in cancer cells. Full article
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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