microtubule assembly
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2022 ◽  
Vol 29 ◽  
pp. 101199
Author(s):  
R. Wu ◽  
J.R. Guzman-Sepulveda ◽  
A.P. Kalra ◽  
J.A. Tuszynski ◽  
A. Dogariu

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Yun Yang ◽  
Victor Tapias ◽  
Diana Acosta ◽  
Hui Xu ◽  
Huanlian Chen ◽  
...  

AbstractAbnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.


2022 ◽  
Vol 221 (3) ◽  
Author(s):  
Sophia M. Hirsch ◽  
Frances Edwards ◽  
Mimi Shirasu-Hiza ◽  
Julien Dumont ◽  
Julie C. Canman

Contractile ring constriction during cytokinesis is thought to compact central spindle microtubules to form the midbody, an antiparallel microtubule bundle at the intercellular bridge. In Caenorhabditis elegans, central spindle microtubule assembly requires targeting of the CLASP family protein CLS-2 to the kinetochores in metaphase and spindle midzone in anaphase. CLS-2 targeting is mediated by the CENP-F–like HCP-1/2, but their roles in cytokinesis and midbody assembly are not known. We found that although HCP-1 and HCP-2 mostly function cooperatively, HCP-1 plays a more primary role in promoting CLS-2–dependent central spindle microtubule assembly. HCP-1/2 codisrupted embryos did not form central spindles but completed cytokinesis and formed functional midbodies capable of supporting abscission. These central spindle–independent midbodies appeared to form via contractile ring constriction–driven bundling of astral microtubules at the furrow tip. This work suggests that, in the absence of a central spindle, astral microtubules can support midbody assembly and that midbody assembly is more predictive of successful cytokinesis than central spindle assembly.


Author(s):  
Neda Sahi ◽  
Akbar Mostajeran ◽  
Mustafa Ghanadian

Catharanthus roseus seedling was treated with different concentrations (1.5, 3.16, 15, and 30 mmol) and forms (K<sub>2</sub>SO<sub>4</sub> and KNO<sub>3</sub>) of potassium (K<sup>+</sup>) via Hoagland’s nutrient solution. Ascorbic acid (AsA) was sprayed twice (plant days 68 and 78) with different concentrations (750 and 1 500 mg/L) on the leaves. Vinblastine, vincristine, tryptophan contents, D4H and DAT genes expression, peroxidase activity, and H<sub>2</sub>O<sub>2</sub> content of leaves were measured. Potassium in KNO<sub>3</sub> form increased vinblastine (60%) and vincristine (50%), compared to 30% and 20% using K<sub>2</sub>SO<sub>4</sub>. Vinblastine and vincristine inhibit microtubule assembly and ultimately metaphase-arrested caused by the polymerisation. The genes expression was higher 3 times in KNO<sub>3</sub> and 2.5 times in K<sub>2</sub>SO<sub>4</sub> in excess of K<sup>+</sup>. Foliar application of 750 mg/L AsA led to an increase in vinblastine (20%) and vincristine (16%). Both concentrations of AsA had the same additional effect on the expression of D4H and DAT about 30% and 60%, respectively, compared to the control plant. Tryptophan decreased 2.5 times in excess of K<sup>+</sup> and 35% due to the exterior of AsA. H<sub>2</sub>O<sub>2</sub> decreased while peroxidase activity increased along with AsA treatment. A positive interaction existed between the K<sup>+</sup> and AsA on the amount of vinblastine, vincristine, tryptophan, and gene expression.  


Morphologia ◽  
2021 ◽  
Vol 15 (1) ◽  
pp. 92-98
Author(s):  
Abraham L Kierszenbaum M.D. Ph.D., Laura Tres M.D. Ph.D.

Linking basic science to clinical application throughout, Histology and Cell Biology: An Introduction to Pathology, 5th Edition, helps students build a stronger clinical knowledge base in the challenging area of pathologic abnormalities. This award-winning text presents key concepts in an understandable, easy-to-understand manner, with full-color illustrations, diagrams, photomicrographs, and pathology photos fully integrated on every page. Student-friendly features such as highlighted clinical terms, Clinical Conditions boxes, Essential Concepts boxes, concept mapping animations, and more help readers quickly grasp complex information. Features new content on cancer immunotherapy, satellite cells and muscle repair, vasculogenesis and angiogenesis in relation to cancer treatment, and mitochondria replacement therapies. Presents new material on ciliogenesis, microtubule assembly and disassembly, chromatin structure and condensation, and X chromosome inactivation, which directly impact therapy for ciliopathies, infertility, cancer, and Alzheimer’s disease. Provides thoroughly updated information on gestational trophoblastic diseases, molecular aspects of breast cancer, and basic immunology, including new illustrations on the structure of the T-cell receptor, CD4+ cells subtypes and functions, and the structure of the human spleen. Uses a new, light green background throughout the text to identify essential concepts of histology – a feature requested by both students and instructors to quickly locate which concepts are most important for beginning learners or when time is limited. These essential concepts are followed by more detailed information on cell biology and pathology. Contains new Primers in most chapters that provide a practical, self-contained integration of histology, cell biology, and pathology – perfect for clarifying the relationship between basic and clinical sciences. Identifies clinical terms throughout the text and lists all clinical boxes in the table of contents for quick reference. Helps students understand the links between chapter concepts with concept mapping animations on Student Consult™ – an outstanding supplement to in-class instruction. Student Consult™ eBook version included with purchase. This enhanced eBook experience allows you to search all of the text, figures, and references from the book on a variety of devices.


2021 ◽  
Author(s):  
Shahan Mamoor

Women diagnosed with triple negative breast cancer can benefit neither from endocrine therapy nor from HER2-targeted therapies (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding abnormal spindle microtubule assembly, ASPM, when comparing the tumor cells of patients with triple negative breast cancer to normal mammary ductal cells (2). ASPM was also differentially expressed in bulk tumor in human breast cancer (3). ASPM mRNA was present at significantly increased quantities in TNBC tumor cells relative to normal mammary ductal cells. Analysis of human survival data revealed that expression of ASPM in primary tumors of the breast was correlated with recurrence-free survival in patients with basal-like and luminal A type cancer, while within triple negative breast cancer, primary tumor expression of ASPM was correlated with overall survival in patients with basal-like 1 subtype disease. ASPM may be of relevance to initiation, maintenance or progression of triple negative breast cancers.


2021 ◽  
Vol 14 (11) ◽  
pp. 1114
Author(s):  
Momen R. Fareed ◽  
Mai E. Shoman ◽  
Mohammed I. A. Hamed ◽  
Mohamed Badr ◽  
Hanin A. Bogari ◽  
...  

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC50 = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.


2021 ◽  
Author(s):  
Xingjun Meng ◽  
Zhihui Cao ◽  
Renfeng Liu ◽  
Kai Zheng ◽  
Shuai Ding ◽  
...  

Abstract It is widely accepted that tumor metastasis is the dominant factor leading to cancer-related death. Tumor metastasis is mediated by cell invasion, blood circulation and lymphatic circulation. Paclitaxel, as a common anti-tumor drug and a mitotic inhibitor, promotes microtubule assembly and inhibits microtubule depolymerization. In addition, ticagrelor, an anti-platelet drug, is used to treat acute coronary syndrome. An increasing numbers of studies have reported that platelets can facilitate tumor metastasis. Therefore, inhibiting the effects of platelets can serve as a novel therapeutic strategy for cancer. To explore the effect of anti-tumor and anti-platelet drugs on tumor progression, the murine melanoma cell line, B16F10, and Lewis Lung carcinoma (LLC) cells were treated with paclitaxel and/or ticagrelor. Interestingly, the results demonstrated that paclitaxel and ticagrelor could not only suppress the proliferation, migration and invasion of B16F10 and LLC cells, but they could also prevent tumor metastasis to the lungs. Furthermore, the inhibitory effect of paclitaxel and ticagrelor was more apparent when both drugs were used in combination. Collectively, the current study demonstrated that the combination of paclitaxel and ticagrelor could be considered as a potential anti-tumor therapy approach.


2021 ◽  
Author(s):  
Valérie Campanacci ◽  
Agathe Urvoas ◽  
Liza Ammar Khodja ◽  
Magali Aumont-Nicaise ◽  
Magali Noiray ◽  
...  

Microtubule dynamics is regulated by various cellular proteins and perturbed by small molecule compounds. To what extent the mechanism of the former resembles that of the latter is an open question. We report here structures of tubulin bound to the PN2-3 domain of CPAP, a protein controlling the length of the centrioles. We show that an α-helix of the PN2-3 N-terminal region binds and caps the longitudinal surface of the tubulin β subunit. Moreover, a PN2-3 N-terminal stretch lies in a β-tubulin site also targeted by fungal and bacterial peptide-like inhibitors of the vinca domain, sharing a very similar binding mode with these compounds. Therefore, our results identify several characteristic features of cellular partners that bind to this site and highlight a structural convergence of CPAP with small molecules inhibitors of microtubule assembly.


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