microtubule network
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2022 ◽  
Vol 2022 ◽  
pp. 1-11
Author(s):  
Farzin Hadizadeh ◽  
Razieh Ghodsi ◽  
Salimeh Mirzaei ◽  
Amirhossein Sahebkar

Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner–Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.


2022 ◽  
Author(s):  
Matthew R Hannaford ◽  
Rong Liu ◽  
Neil Billington ◽  
Zachary T Swider ◽  
Brian J Galletta ◽  
...  

Centrosome positioning is essential for their function. Typically, centrosomes are transported to various cellular locations through the interaction of centrosome nucleated microtubules with motor proteins. However, it remains unknown how centrioles migrate in cellular contexts in which centrioles do not nucleate microtubules. Here, we demonstrate that during interphase inactive centrioles move directly along the noncentrosomal microtubule network as cargo for the motor protein Kinesin-1. We identify Pericentrin-Like-Protein (PLP) as a novel Kinesin-1 interacting molecule essential for centriole motility. PLP directly interacts with the cargo binding domain of Kinesin-1 and they comigrate on microtubules in vitro. Finally, we demonstrate that PLP-Kinesin-1 dependent transport is essential for centrosome asymmetry age dependent centrosome inheritance in asymmetric stem cell division.


Author(s):  
Debasish Halder ◽  
Su-Jin Jeon ◽  
Ji-Yong Yoon ◽  
Jeong-Ju Lee ◽  
Soo Young Jun ◽  
...  

AbstractTREX1 is an exonuclease that degrades extranuclear DNA species in mammalian cells. Herein, we show a novel mechanism by which TREX1 interacts with the BiP/GRP78 and TREX1 deficiency triggers ER stress through the accumulation of single-stranded DNA and activates unfolded protein response (UPR) signaling via the disruption of the TREX1-BiP/GRP78 interaction. In TREX1 knockdown cells, the activation of ER stress signaling disrupted ER Ca2+ homeostasis via the ERO1α-IP3R1-CaMKII pathway, leading to neuronal cell death. Moreover, TREX1 knockdown dysregulated the Golgi-microtubule network through Golgi fragmentation and decreased Ac-α-tubulin levels, contributing to neuronal injury. These alterations were also observed in neuronal cells harboring a TREX1 mutation (V91M) that has been identified in hereditary spastic paraplegia (HSP) patients in Korea. Notably, this mutation leads to defects in the TREX1-BiP/GRP78 interaction and mislocalization of TREX1 from the ER and possible disruption of the Golgi-microtubule network. In summary, the current study reveals TREX1 as a novel regulator of the BiP/GRP78 interaction and shows that TREX1 deficiency promotes ER stress-mediated neuronal cell death, which indicates that TREX1 may hold promise as a therapeutic target for neurodegenerative diseases such as HSP.


Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 15
Author(s):  
Azumi Yoshimura ◽  
Stéphanie Miserey-Lenkei ◽  
Evelyne Coudrier ◽  
Bruno Goud

In the early secretory pathway, the delivery of anterograde cargoes from the endoplasmic reticulum (ER) exit sites (ERES) to the Golgi apparatus is a multi-step transport process occurring via the ER-Golgi intermediate compartment (IC, also called ERGIC). While the role microtubules in ER-to-Golgi transport has been well established, how the actin cytoskeleton contributes to this process remains poorly understood. Here, we report that Arp2/3 inhibition affects the network of acetylated microtubules around the Golgi and induces the accumulation of unusually long RAB1/GM130-positive carriers around the centrosome. These long carriers are less prone to reach the Golgi apparatus, and arrival of anterograde cargoes to the Golgi is decreased upon Arp2/3 inhibition. Our data suggest that Arp2/3-dependent actin polymerization maintains a stable network of acetylated microtubules, which ensures efficient cargo trafficking at the late stage of ER to Golgi transport.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3600
Author(s):  
Min-Jeong Cho ◽  
Yu-Jin Kim ◽  
Won-Dong Yu ◽  
You-Sin Kim ◽  
Jae-Ho Lee

Mitochondria move along the microtubule network and produce bioenergy in the cell. However, there is no report of a relationship between bioenergetic activity of mitochondria and microtubule stability in mammalian cells. This study aimed to investigate this relationship. We treated HEK293 cells with microtubule stabilizers (Taxol and Epothilone D) or a microtubule disturber (vinorelbine), and performed live-cell imaging to determine whether mitochondrial morphology and bioenergetic activity depend on the microtubule status. Treatment with microtubule stabilizers enhanced the staining intensity of microtubules, significantly increased ATP production and the spare respiratory capacity, dramatically increased mitochondrial fusion, and promoted dynamic movement of mitochondria. By contrast, bioenergetic activity of mitochondria was significantly decreased in cells treated with the microtubule disturber. Our data suggest that microtubule stability promotes mitochondrial functional activity. In conclusion, a microtubule stabilizer can possibly recover mitochondrial functional activity in cells with unstable microtubules.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Patrick Stoiber ◽  
Pietro Scribani Rossi ◽  
Niranjana Pokharel ◽  
Jean-Luc Germany ◽  
Emily A. York ◽  
...  

AbstractFactor quinolinone inhibitors are promising anti-cancer compounds, initially characterized as specific inhibitors of the oncogenic transcription factor LSF (TFCP2). These compounds exert anti-proliferative activity at least in part by disrupting mitotic spindles. Herein, we report additional interphase consequences of the initial lead compound, FQI1, in two telomerase immortalized cell lines. Within minutes of FQI1 addition, the microtubule network is disrupted, resulting in a substantial, although not complete, depletion of microtubules as evidenced both by microtubule sedimentation assays and microscopy. Surprisingly, this microtubule breakdown is quickly followed by an increase in tubulin acetylation in the remaining microtubules. The sudden breakdown and partial depolymerization of the microtubule network precedes FQI1-induced morphological changes. These involve rapid reduction of cell spreading of interphase fetal hepatocytes and increase in circularity of retinal pigment epithelial cells. Microtubule depolymerization gives rise to FH-B cell compaction, as pretreatment with taxol prevents this morphological change. Finally, FQI1 decreases the rate and range of locomotion of interphase cells, supporting an impact of FQI1-induced microtubule breakdown on cell motility. Taken together, our results show that FQI1 interferes with microtubule-associated functions in interphase, specifically cell morphology and motility.


2021 ◽  
Author(s):  
◽  
Marcus James Robinson

<p>The microtubule network is involved in cellular processes including protein transport and cell division. Microtubule stabilising drugs (MSD) bind to microtubules and alter their dynamic balance in favour of the polymerised state. While primarily known for their anti-mitotic properties, MSD also exert immunomodulatory effects in vitro and in vivo. It is the aim of this project to investigate the effects of MSD on protein trafficking and secretion to determine how they affect immune-mediated exocytosis. Previous work in our lab demonstrated that macrophage responses to bacterial lipopolysaccharide, as measured by the production of TNF-a and nitric oxide, are inhibited by both paclitaxel and peloruside. In this thesis we continued this work and saw that inhibition was not affected by temporal IFN-y priming and found that altered production kinetics were not sufficient to explain the inhibition. To kill target cells cytotoxic T cells (CTL) reorganise their cytoskeleton so that lytic granules can traffic down microtubules to be delivered to the target. Using an in vitro model of CTL killing, we saw that MSD did not inhibit killing by CTL, lytic granule delivery to the cell surface, or antigen-stimulated Interferon-y (IFN-y) production by CTL. In contrast to this, in a murine model of antigen-induced killing we saw that a single dose of paclitaxel had a significant inhibitory effect on CTL-mediated cytolysis in vivo. Together these studies suggest that MSD have multiple immunomodulatory effects that are independent of their anti-proliferative effects. The data suggest that patients undergoing taxane therapy may be unable to fight infection long before the anti-mitotic effects of MSD are apparent.</p>


2021 ◽  
Author(s):  
◽  
Marcus James Robinson

<p>The microtubule network is involved in cellular processes including protein transport and cell division. Microtubule stabilising drugs (MSD) bind to microtubules and alter their dynamic balance in favour of the polymerised state. While primarily known for their anti-mitotic properties, MSD also exert immunomodulatory effects in vitro and in vivo. It is the aim of this project to investigate the effects of MSD on protein trafficking and secretion to determine how they affect immune-mediated exocytosis. Previous work in our lab demonstrated that macrophage responses to bacterial lipopolysaccharide, as measured by the production of TNF-a and nitric oxide, are inhibited by both paclitaxel and peloruside. In this thesis we continued this work and saw that inhibition was not affected by temporal IFN-y priming and found that altered production kinetics were not sufficient to explain the inhibition. To kill target cells cytotoxic T cells (CTL) reorganise their cytoskeleton so that lytic granules can traffic down microtubules to be delivered to the target. Using an in vitro model of CTL killing, we saw that MSD did not inhibit killing by CTL, lytic granule delivery to the cell surface, or antigen-stimulated Interferon-y (IFN-y) production by CTL. In contrast to this, in a murine model of antigen-induced killing we saw that a single dose of paclitaxel had a significant inhibitory effect on CTL-mediated cytolysis in vivo. Together these studies suggest that MSD have multiple immunomodulatory effects that are independent of their anti-proliferative effects. The data suggest that patients undergoing taxane therapy may be unable to fight infection long before the anti-mitotic effects of MSD are apparent.</p>


2021 ◽  
Vol 12 ◽  
Author(s):  
Yi-Ting Huang ◽  
Ya-Ting Hsu ◽  
Yih-Fung Chen ◽  
Meng-Ru Shen

Store-operated Ca2+ entry (SOCE) is an essential pathway for Ca2+ signaling, and regulates various vital cellular functions. It is triggered by the endoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1). Illustration of STIM1 spatiotemporal structure at the nanometer scale during SOCE activation provides structural and functional insights into the fundamental Ca2+ homeostasis. In this study, we used direct stochastic optical reconstruction microscopy (dSTORM) to revisit the dynamic process of the interaction between STIM1, end-binding protein (EB), and microtubules to the ER-plasma membrane. Using dSTORM, we found that“powder-like”STIM1 aggregates into “trabecular-like” architectures toward the cell periphery during SOCE, and that an intact microtubule network and EB1 are essential for STIM1 trafficking. After thapsigargin treatment, STIM1 can interact with EB1 regardless of undergoing aggregation. We generated STIM1 variants adapted from a real-world database and introduced them into SiHa cells to clarify the impact of STIM1 mutations on cancer cell behavior. The p.D76G and p.D84Y variants locating on the Ca2+ binding domain of STIM1 result in inhibition of focal adhesion turnover, Ca2+ influx during SOCE and subsequent cell migration. Inversely, the p.R643C variant on the microtubule interacting domain of STIM1 leads to dissimilar consequence and aggravates cell migration. These findings imply that STIM1 mutational patterns have an impact on cancer metastasis, and therefore could be either a prognostic marker or a novel therapeutic target to inhibit the malignant behavior of STIM1-mediated cancer cells. Altogether, we generated novel insight into the role of STIM1 during SOCE activation, and uncovered the impact of real-world STIM1 variants on cancer cells.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lance T. Denes ◽  
Chase P. Kelley ◽  
Eric T. Wang

AbstractWhile the importance of RNA localization in highly differentiated cells is well appreciated, basic principles of RNA localization in skeletal muscle remain poorly characterized. Here, we develop a method to detect and quantify single molecule RNA localization patterns in skeletal myofibers, and uncover a critical role for directed transport of RNPs in muscle. We find that RNAs localize and are translated along sarcomere Z-disks, dispersing tens of microns from progenitor nuclei, regardless of encoded protein function. We find that directed transport along the lattice-like microtubule network of myofibers becomes essential to achieve this localization pattern as muscle development progresses; disruption of this network leads to extreme accumulation of RNPs and nascent protein around myonuclei. Our observations suggest that global active RNP transport may be required to distribute RNAs in highly differentiated cells and reveal fundamental mechanisms of gene regulation, with consequences for myopathies caused by perturbations to RNPs or microtubules.


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