scholarly journals Tubulin: Structure, Functions and Roles in Disease

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1294 ◽  
Author(s):  
Pavla Binarová ◽  
Jack Tuszynski
Keyword(s):  
Cell Cycle ◽  
Allergic Diseases ◽  
Structure Functions ◽  
Original Research ◽  
Cellular Functions ◽  
Microtubule Nucleation ◽  
Post Translational Modifications ◽  
Tubulin Isotypes ◽  
Structural Support ◽  
Tubulin Structure

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.

Tubulin heterogeneity regulates functions and dynamics of microtubules and plays a role in the development of drug resistance in cancer

2019 ◽  
Vol 476 (9) ◽  
pp. 1359-1376 ◽  
Author(s):  
Shweta Shyam Prassanawar ◽  
Dulal Panda
Keyword(s):  
Current Knowledge ◽  
Cell Types ◽  
Cellular Functions ◽  
Spatial Cues ◽  
Post Translational Modifications ◽  
Tubulin Isotypes ◽  
Development Of Resistance ◽  
Structural And Functional Properties ◽  
Differential Stability ◽  
Different Cell Types

Abstract Microtubules, composed of αβ-tubulin heterodimers, exhibit diverse structural and functional properties in different cell types. The diversity in the microtubule structure originates from tubulin heterogeneities, namely tubulin isotypes and their post-translational modifications (PTMs). These heterogeneities confer differential stability to microtubules and provide spatial cues for the functioning of the cell. Furthermore, the altered expressions of tubulin isotypes and PTMs are prominent factors for the development of resistance against some cancer drugs. In this review, we summarize our current knowledge of the tubulin isotypes and PTMs and how, together, they control the cellular functions of the microtubules. We also describe how cancer cells use this tubulin heterogeneity to acquire resistance against clinical agents and discuss existing attempts to counter the developed resistance.

scholarly journals Immunological discrimination of β-tubulin isoforms in developing mouse brain. Post-translational modification of non-class-III β-tubulins

1992 ◽  
Vol 288 (3) ◽  
pp. 919-924 ◽  
Author(s):  
I Linhartová ◽  
P Dráber ◽  
E Dráberová ◽  
V Viklický
Keyword(s):  
Mouse Brain ◽  
Specific Class ◽  
Class Iii ◽  
Post Translational Modification ◽  
Beta Tubulin ◽  
Developmentally Regulated ◽  
Post Translational Modifications ◽  
Tubulin Isotypes ◽  
Tubulin Isoforms ◽  
Developing Mouse Brain

Individual beta-tubulin isoforms in developing mouse brain were characterized using immunoblotting, after preceding high-resolution isoelectric focusing, with monoclonal antibodies against different structural regions of beta-tubulin. Some of the antibodies reacted with a limited number of tubulin isoforms in all stages of brain development and in HeLa cells. The epitope for the TU-14 antibody was located in the isotype-defining domain and was present on the beta-tubulin isotypes of classes I, II and IV, but absent on the neuron-specific class-III isotype. The data suggest that non-class-III beta-tubulins in mouse brain are substrates for developmentally regulated post-translational modifications and that beta-tubulins of non-neuronal cells are also post-translationally modified.

scholarly journals Phosphorylation of RCC1 on Serine 11 Facilitates G1/S Transition in HPV E7-Expressing Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 995
Author(s):  
Xiaoyan Hou ◽  
Lijun Qiao ◽  
Ruijuan Liu ◽  
Xuechao Han ◽  
Weifang Zhang
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Mtor Pathway ◽  
Cycle Progression ◽  
Post Translational Modifications ◽  
Hpv E7 ◽  
Cycle Regulation

Persistent infection of high-risk human papillomavirus (HR-HPV) plays a causal role in cervical cancer. Regulator of chromosome condensation 1 (RCC1) is a critical cell cycle regulator, which undergoes a few post-translational modifications including phosphorylation. Here, we showed that serine 11 (S11) of RCC1 was phosphorylated in HPV E7-expressing cells. However, S11 phosphorylation was not up-regulated by CDK1 in E7-expressing cells; instead, the PI3K/AKT/mTOR pathway promoted S11 phosphorylation. Knockdown of AKT or inhibition of the PI3K/AKT/mTOR pathway down-regulated phosphorylation of RCC1 S11. Furthermore, S11 phosphorylation occurred throughout the cell cycle, and reached its peak during the mitosis phase. Our previous data proved that RCC1 was necessary for the G1/S cell cycle progression, and in the present study we showed that the RCC1 mutant, in which S11 was mutated to alanine (S11A) to mimic non-phosphorylation status, lost the ability to facilitate G1/S transition in E7-expressing cells. Moreover, RCC1 S11 was phosphorylated by the PI3K/AKT/mTOR pathway in HPV-positive cervical cancer SiHa and HeLa cells. We conclude that S11 of RCC1 is phosphorylated by the PI3K/AKT/mTOR pathway and phosphorylation of RCC1 S11 facilitates the abrogation of G1 checkpoint in HPV E7-expressing cells. In short, our study explores a new role of RCC1 S11 phosphorylation in cell cycle regulation.

scholarly journals In-Frame and Frameshift Mutations in Zebrafish presenilin 2 Affect Different Cellular Functions in Young Adult Brains

2021 ◽  
pp. 1-10
Author(s):  
Karissa Barthelson ◽  
Stephen Martin Pederson ◽  
Morgan Newman ◽  
Haowei Jiang ◽  
Michael Lardelli
Keyword(s):  
Cell Cycle ◽  
Young Adult ◽  
Oxidative Phosphorylation ◽  
Frameshift Mutation ◽  
Long Term Potentiation ◽  
Cellular Functions ◽  
Reading Frame ◽  
Term Potentiation ◽  
Presenilin 2

Background: Mutations in PRESENILIN 2 (PSEN2) cause early onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon—the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated. Objective: To predict cellular functions affected by heterozygosity for a frameshift, or a reading frame-preserving mutation in zebrafish psen2 using bioinformatic techniques. Methods: A frameshift mutation (psen2N140fs) and a reading frame-preserving (in-frame) mutation (psen2T141 _ L142delinsMISLISV) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analyzed. Results: The in-frame mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long-term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signaling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions. Conclusion: A frameshift and an in-frame mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long-term potentiation and the cell cycle may promote EOfAD pathogenesis in humans.

scholarly journals TFEB Signalling-Related MicroRNAs and Autophagy

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 985
Author(s):  
Davide Corà ◽  
Federico Bussolino ◽  
Gabriella Doronzo
Keyword(s):  
Transcriptional Regulation ◽  
Stress Factors ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Factor Deficiency ◽  
Transcription Factor Eb ◽  
Important Regulator ◽  
Response To Stress ◽  
Post Transcriptional Regulation

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.

Association of cyclin-bound p34cdc2 with subcellular structures in xenopus eggs

1992 ◽  
Vol 102 (2) ◽  
pp. 285-297 ◽  
Author(s):  
D. Leiss ◽  
M.A. Felix ◽  
E. Karsenti
Keyword(s):  
Cell Cycle ◽  
Ribosomal Proteins ◽  
Cell Cycle Progression ◽  
Gradient Centrifugation ◽  
Preliminary Evidence ◽  
Embryonic Cell ◽  
Cytoskeletal Proteins ◽  
Cyclin B ◽  
Post Translational Modifications ◽  
Egg Extracts

Cell cycle progression is controlled by changes in kinase activity of homologs of the fission yeast protein p34cdc2. The p34cdc2 kinase is activated by its association with a cyclin subunit, followed by post-translational modifications. Here, we show that in Xenopus eggs stimulated to enter the early embryonic cell cycle by an electric shock, part of the p34cdc2 becomes associated with subcellular fractions as the eggs progress towards mitosis. This occurs as a result of cyclin accumulation because most of the B-type cyclins and some of the A-type cyclins are found in the particulate fraction. Moreover, as soon as cyclins are degraded, p34cdc2 is released in the soluble fraction. The p34cdc2-cyclin complex can be solubilised by 80 mM beta-glycerophosphate (in the standard MPF extraction buffer) or by high salt concentrations. The post-translational modifications leading to cdc2 kinase activation by cyclin occur in the insoluble form. Following fractionation of egg extracts by sucrose gradient centrifugation, the p34cdc2-cyclin B complex is found in several fractions, but especially in two discrete peaks. We present evidence that in the slow-sedimenting peak the p34cdc2-cyclin B complex is associated with the 60 S subunit of monoribosomes. It could be targeted in this fashion to substrates such as ribosomal proteins and maybe to cytoskeletal proteins, since ribosomes bind to microtubules and are present in the spindle. The p34cdc2-cyclin B complex is also found in a faster-migrating fraction containing various membranous structures, including Golgi stacks. Therefore, as observed by immunofluorescence in other systems, it seems that cyclin subunits target p34cdc2 to specific cellular sites and this is certainly important for its function. In addition, we present preliminary evidence suggesting that some component present in the ribosome-containing fraction is required for activation of the p34cdc2-cyclin B complex.

scholarly journals Allosteric changes in HDM2 by the ATM phosphomimetic S395D mutation: implications on HDM2 function

2019 ◽  
Vol 476 (21) ◽  
pp. 3401-3411 ◽  
Author(s):  
Lukas Uhrik ◽  
Lixiao Wang ◽  
Lucia Haronikova ◽  
Ixaura Medina-Medina ◽  
Yolanda Rebolloso-Gomez ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
P53 Protein ◽  
Intrinsic Disorder ◽  
26S Proteasome ◽  
Ataxia Telangiectasia Mutated ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Positive Regulator ◽  
P53 Mrna

Allosteric changes imposed by post-translational modifications regulate and differentiate the functions of proteins with intrinsic disorder regions. HDM2 is a hub protein with a large interactome and with different cellular functions. It is best known for its regulation of the p53 tumour suppressor. Under normal cellular conditions, HDM2 ubiquitinates and degrades p53 by the 26S proteasome but after DNA damage, HDM2 switches from a negative to a positive regulator of p53 by binding to p53 mRNA to promote translation of the p53 mRNA. This change in activity is governed by the ataxia telangiectasia mutated kinase via phosphorylation on serine 395 and is mimicked by the S395D phosphomimetic mutant. Here we have used different approaches to show that this event is accompanied by a specific change in the HDM2 structure that affects the HDM2 interactome, such as the N-termini HDM2–p53 protein–protein interaction. These data will give a better understanding of how HDM2 switches from a negative to a positive regulator of p53 and gain new insights into the control of the HDM2 structure and its interactome under different cellular conditions and help identify interphases as potential targets for new drug developments.

scholarly journals ECM-LSE: Prediction of Extracellular Matrix Proteins Using Deep Latent Space Encoding of k-Spaced Amino Acid Pairs

2021 ◽  
Vol 9 ◽  
Author(s):  
Ubaid M. Al-Saggaf ◽  
Muhammad Usman ◽  
Imran Naseem ◽  
Muhammad Moinuddin ◽  
Ahmad A. Jiman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Vital Role ◽  
Cellular Functions ◽  
Structural Support ◽  
Ecm Proteins ◽  
Latent Space ◽  
Machine Learning Approach ◽  
Wet Lab ◽  
Living Tissues ◽  
Space Encoding

Extracelluar matrix (ECM) proteins create complex networks of macromolecules which fill-in the extracellular spaces of living tissues. They provide structural support and play an important role in maintaining cellular functions. Identification of ECM proteins can play a vital role in studying various types of diseases. Conventional wet lab–based methods are reliable; however, they are expensive and time consuming and are, therefore, not scalable. In this research, we propose a sequence-based novel machine learning approach for the prediction of ECM proteins. In the proposed method, composition of k-spaced amino acid pair (CKSAAP) features are encoded into a classifiable latent space (LS) with the help of deep latent space encoding (LSE). A comprehensive ablation analysis is conducted for performance evaluation of the proposed method. Results are compared with other state-of-the-art methods on the benchmark dataset, and the proposed ECM-LSE approach has shown to comprehensively outperform the contemporary methods.

scholarly journals Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity

Development ◽  
2001 ◽  
Vol 128 (9) ◽  
pp. 1687-1696 ◽  
Author(s):  
K. Halfar ◽  
C. Rommel ◽  
H. Stocker ◽  
E. Hafen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Photoreceptor Cells ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Partial Loss ◽  
Cycle Progression ◽  
Mapk Activity ◽  
Dividing Cells

Ras mediates a plethora of cellular functions during development. In the developing eye of Drosophila, Ras performs three temporally separate functions. In dividing cells, it is required for growth but is not essential for cell cycle progression. In postmitotic cells, it promotes survival and subsequent differentiation of ommatidial cells. In the present paper, we have analyzed the different roles of Ras during eye development by using molecularly defined complete and partial loss-of-function mutations of Ras. We show that the three different functions of Ras are mediated by distinct thresholds of MAPK activity. Low MAPK activity prolongs cell survival and permits differentiation of R8 photoreceptor cells while high or persistent MAPK activity is sufficient to precociously induce R1-R7 photoreceptor differentiation in dividing cells.

scholarly journals C-terminal tail polyglycylation and polyglutamylation alter microtubule mechanical properties

2019 ◽  
Author(s):  
Kathryn P. Wall ◽  
Harold Hart ◽  
Thomas Lee ◽  
Cynthia Page ◽  
Taviare L. Hawkins ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Molecular Mechanisms ◽  
High Stress ◽  
Resonance Spectroscopy ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Peptide Backbone ◽  
Post Translational Modifications ◽  
Intrinsic Stiffness ◽  
Insight Into

ABSTRACTMicrotubules are biopolymers that perform diverse cellular functions. The regulation of microtubule behavior occurs in part through post-translational modification of both the α- and β- subunits of tubulin. One class of modifications is the heterogeneous addition of glycine and glutamate residues to the disordered C-terminal tails of tubulin. Due to their prevalence in stable, high stress cellular structures such as cilia, we sought to determine if these modifications alter the intrinsic stiffness of microtubules. Here we describe the purification and characterization of differentially-modified pools of tubulin from Tetrahymena thermophila. We found that glycylation on the α-C-terminal tail is a key determinant of microtubule stiffness, but does not affect the number of protofilaments incorporated into microtubules. We measured the dynamics of the tail peptide backbone using nuclear magnetic resonance spectroscopy. We found that the spin-spin relaxation rate (R2) showed a pronounced decreased as a function of distance from the tubulin surface for the α-tubulin tail, indicating that the α-tubulin tail interacts with the dimer surface. This suggests that the interactions of the α-C-terminal tail with the tubulin body contributes to the stiffness of the assembled microtubule, providing insight into the mechanism by which glycylation and glutamylation can alter microtubule mechanical properties.SIGNIFICANCEMicrotubules are regulated in part by post-translational modifications including the heterogeneous addition of glycine and glutamate residues to the C-terminal tails. By producing and characterizing differentially-modified tubulin, this work provides insight into the molecular mechanisms of how these modifications alter intrinsic microtubule properties such as flexibility. These results have broader implications for mechanisms of how ciliary structures are able to function under high stress.

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