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Ángel M Montaña, Julia Lorenzo, Stefano Ponzano, Maria-Filomena Sanasi
This article describes the design, synthesis and biological evaluation of a new family of antitumor agents having the 1,7-epoxycyclononane framework. We have developed a versatile synthetic methodology that allows the preparation of a chemical library with structural diversity and in good yield. The synthetic methodology has been scaled up to the multigram level and can be developed in an enantioselective fashion. The study in vitro of a model compound, in front of the cancer cell lines HL-60 and MCF-7, showed a growth inhibitory effect better than that of cisplatin...
May 18, 2018: Bioorganic & Medicinal Chemistry
Asako Shindo, Anastasia Audrey, Maki Takagishi, Masahide Takahashi, John B Wallingford, Makoto Kinoshita
Wounds in embryos heal rapidly through the contraction of the wound edges. Despite well-recognized significance of the actomyosin purse-string for wound closure, roles for other cytoskeletal components are largely unknown. Here, we report that the septin cytoskeleton cooperates with actomyosin and microtubules to coordinate circumferential contraction of the wound margin and concentric elongation of wound-proximal cells in Xenopus laevis embryos. Microtubules reoriented radially, forming bundles along lateral cell cortices in elongating wound-proximal cells...
May 18, 2018: Journal of Cell Science
Michael J Bond, Marina Bleiler, Lauren E Harrison, Eric W Scocchera, Masako Nakanishi, Narendran G-Dayanandan, Santosh Keshipeddy, Daniel W Rosenberg, Dennis L Wright, Charles Giardina
AK3 compounds are mitotic-arrest agents that induce high levels of γH2AX during mitosis and apoptosis following release from arrest. We synthesized a potent AK3 derivative, AK306, that induced arrest and apoptosis of the HCT116 colon cancer cell line with an EC50 of ~50 nM. AK306 was active on a broad spectrum of cancer cell lines with total growth inhibition values ranging from ~25 nM to 25 µM. Using biotin and BODIPY-linked derivatives of AK306, binding to clathrin heavy chain (CLTC/CHC) was observed, a protein with roles in endocytosis and mitosis...
May 16, 2018: Molecular Cancer Research: MCR
Hailu Fu, Huijun Gao, Xiaoyu Qi, Lei Zhao, Donghua Wu, Yuxin Bai, Huimin Li, Xuan Liu, Jun Hu, Shujuan Shao
BACKGROUND: Our previous study demonstrated that aldolase A (ALDOA) is overexpressed in clinical human lung squamous cell carcinoma and that ALDOA promotes epithelial-mesenchymal transition and tumorigenesis. The present study aimed to explore the function of ALDOA in the modulation of non-small cell lung cancer (NSCLC) proliferation and cell cycle progression and the potential mechanism. METHODS: ALDOA was knocked down by short hairpin RNA in H520 and H1299 cells...
May 8, 2018: Cancer communications
Hsin-Pai Li, Chen-Ching Peng, Chih-Ching Wu, Chien-Hsun Chen, Meng-Jhe Shih, Mei-Yuan Huang, Yi-Ru Lai, Yung-Li Chen, Ting-Wen Chen, Petrus Tang, Yu-Sun Chang, Kai-Ping Chang, Cheng-Lung Hsu
BACKGROUND: Aberrant hypermethylation of cellular genes is a common phenomenon to inactivate genes and promote tumorigenesis in nasopharyngeal carcinoma (NPC). METHODS: Methyl binding domain (MBD)-ChIP sequencing of NPC cells, microarray data of NPC biopsies and gene ontology analysis were conducted to identify a potential tumor suppressor gene CLDN11 that was both hypermethylated and downregulated in NPC. Bisulfite sequencing, qRT-PCR, immunohistochemistry staining of the NPC clinical samples and addition of methylation inhibitor, 5'azacytidine, in NPC cells were performed to verify the correlation between DNA hypermethylation and expression of CLDN11...
May 10, 2018: Journal of Experimental & Clinical Cancer Research: CR
Mark D Gurden, Simon J Anderhub, Amir Faisal, Spiros Linardopoulos
Accurate chromosome segregation is dependent on the spindle assembly checkpoint (SAC). In current models, the key direct role of Aurora B in the SAC has been suggested to be to promote rapid kinetochore localisation of MPS1, allowing MPS1 to generate the checkpoint signal. However, Aurora B is also thought to play an indirect role in the SAC through the destabilisation of kinetochore-microtubule (KT-MT) attachments. Here, we demonstrate that Aurora B activity is not required for the kinetochore recruitment of the majority of SAC proteins...
April 13, 2018: Oncotarget
Yiting Yang, Rongmei Qu, Tingyu Fan, Xi Zhu, Yanting Feng, Yuchao Yang, Ting Deng, Yan Peng, Wenhua Huang, Jun Ouyang, Jingxing Dai
BACKGROUND: Adipose-derived stem cells (ASCs) that show multidifferentiation and anti-immune rejection capacities have been widely used in plastic and reconstructive surgery. Previous studies have indicated that mechanical and biophysical interactions between cells and their surrounding environment regulate essential processes, such as growth, survival, and differentiation, and the cytoskeleton system plays an important role in the mechanotransduction. However, the role of mechanical force in the determination of lineage fate is still unclear...
May 2, 2018: Stem Cell Research & Therapy
Yun Yeon Park, Ju-Hyun Ahn, Min-Guk Cho, Jae-Ho Lee
ATP depletion inhibits cell cycle progression, especially during the G1 phase and the G2 to M transition. However, the effect of ATP depletion on mitotic progression remains unclear. We observed that the reduction of ATP after prometaphase by simultaneous treatment with 2-deoxyglucose and NaN3 did not arrest mitotic progression. Interestingly, ATP depletion during nocodazole-induced prometaphase arrest resulted in mitotic slippage, as indicated by a reduction in mitotic cells, APC/C-dependent degradation of cyclin B1, increased cell attachment, and increased nuclear membrane reassembly...
April 27, 2018: Experimental & Molecular Medicine
Chiung-Yueh Hsu, Nicolas Lecland, Valérie Pendaries, Cécile Viodé, Daniel Redoulès, Carle Paul, Andreas Merdes, Michel Simon, Christiane Bierkamp
BACKGROUND: A variety of human skin disorders is characterized by defects in the epidermal barrier, leading to dehydration, itchiness, and rashes. Previously published literature suggests that microtubule stabilization at the cortex of differentiating keratinocytes is necessary for the formation of the epidermal barrier. OBJECTIVES: We tested whether stabilization of microtubules with paclitaxel or epothilone B can repair barrier defects that were experimentally induced in three-dimensional culture models of epidermis...
April 18, 2018: Journal of Dermatological Science
George D Bachand, Rishi Jain, Randy Ko, Nathan F Bouxsein, Virginia VanDelinder
Microtubule dynamics play a critical role in the normal physiology of eukaryotic cells, as well as a number of cancers and neurodegenerative disorders. The polymerization/depolymerization of microtubules is regulated by a variety of stabilizing and destabilizing factors, including microtubule-associated proteins and therapeutic agents (e.g., paclitaxel, nocodazole). Here we describe the ability of the osmolytes polyethylene glycol (PEG) and trimethylamine-N-oxide (TMAO) to inhibit the depolymerization of individual microtubule filaments for extended periods of time (up to 30 days)...
April 24, 2018: Biomacromolecules
Abigail R Gerhold, Vincent Poupart, Jean-Claude Labbé, Paul S Maddox
The spindle assembly checkpoint (SAC) is a conserved mitotic regulator that preserves genome stability by monitoring kinetochore-microtubule attachments and blocking anaphase onset until chromosome bi-orientation is achieved. Despite its central role in maintaining mitotic fidelity, the ability of the SAC to delay mitotic exit in the presence of kinetochore-microtubule attachment defects (SAC "strength") appears to vary widely. How different cellular aspects drive this variation remains largely unknown...
April 24, 2018: Molecular Biology of the Cell
Zerong You, Shuzhuo Zhang, Shiqian Shen, Jinsheng Yang, Weihua Ding, Liuyue Ang, Grewo Lim, Jason T Doheny, Samuel Tate, Lucy Chen, Jianren Mao
Clinical evidence indicates that cognitive impairment is a common comorbid condition of chronic pain. However, the cellular basis for chronic pain-mediated cognitive impairment remains unclear. We report here that rats exhibited memory deficits after spared never injury (SNI). We found that levels of stable microtubule (MT) were increased in the hippocampus of the rats with memory deficits. This increase in stable MT is marked by α-tubulin hyperacetylation. Paclitaxel, a pharmacological MT stabilizer, increased the level of stable MT in the hippocampus and induced learning and memory deficits in normal rats...
April 2, 2018: Pain
Eleni Fegaras, Arthur Forer
A "precocious" cleavage furrow develops and ingresses during early prometaphase in Mesostoma ehrenbergii spermatocytes (Forer and Pickett-Heaps Eur J Cell Biol 89:607-618, 2010). In response to chromosome movements which regularly occur during prometaphase and that alter the balance of chromosomes in the two half-spindles, the precocious furrow shifts its position along the cell, moving 2-3 μm towards the half cell with fewer chromosomes (Ferraro-Gideon et al. Cell Biol Int 37:892-898, 2013). This process continues until proper segregation is achieved and the cell enters anaphase with the cleavage furrow again in the middle of the cell...
March 21, 2018: Protoplasma
Thibault Courtheoux, Alghassimou Diallo, Arun Prasath Damodaran, David Reboutier, Erwan Watrin, Claude Prigent
During the prometaphase stage of mitosis, the cell builds a bipolar spindle of microtubules that mechanically segregates sister chromatids for two daughter cells in anaphase. The spindle assembly checkpoint (SAC) is a quality control mechanism that monitors proper attachment of microtubules to chromosome kinetochores during prometaphase. Segregation occurs only when each chromosome is bi-oriented with each kinetochore pair attached to microtubules emanating from opposite spindle poles. Overexpression of the protein kinase Aurora A is a feature of various cancers and is thought to enable tumour cells to bypass the SAC leading to aneuploidy...
March 19, 2018: Journal of Cell Science
Eleni Fegaras, Arthur Forer
In a typical cell division, chromosomes align at the metaphase plate before anaphase commences. This is not the case in Mesostoma spermatocytes. Throughout prometaphase, the three bivalents persistently oscillate towards and away from either pole, at average speeds of 5-6 μm/min, without ever aligning at a metaphase plate. In our experiments, nocodazole (NOC) was added to prometaphase spermatocytes to depolymerize the microtubules. Traditional theories state that microtubules are the producers of force in the spindle, either by tubulin depolymerizing at the kinetochore (PacMan) or at the pole (Flux)...
February 21, 2018: Protoplasma
Yuka Yamagishi, Kazumasa Oya, Akira Matsuura, Hiroshi Abe
Two types of Arp2/3 complex inhibitors, CK-666/636 and CK-548/869, are commonly used to study Arp2/3 complex-dependent actin assembly both in vitro and in vivo. However, we found that CK-548 and CK-869 directly suppress microtubule (MT) assembly independent of the actin cytoskeleton. Treatment of cultured mammalian cells with 50 μM CK-869 dramatically decreased MT networks and, instead, accumulated tubulin at the cell periphery, as did nocodazole that inhibits MT assembly. An in vitro MT-sedimentation assay revealed that CK-548 and CK-869 significantly suppressed MT polymerization...
February 12, 2018: Biochemical and Biophysical Research Communications
Jing Shen, Jiang-Hui Zhang, Han Xiao, Ji-Min Wu, Kang-Min He, Zhi-Zhen Lv, Zi-Jian Li, Ming Xu, You-Yi Zhang
Membrane nanotubes (MNTs) act as "highways" between cells to facilitate the transfer of multiple signals and play an important role in many diseases. Our previous work reported on the transfer of mitochondria via MNTs between cardiomyocytes (CMs) and cardiac myofibroblasts (MFs); however, the elucidation of the underlying mechanism and pathophysiological significance of this transfer requires additional study. In this study, we determined that the mean movement velocity of mitochondria in MNTs between CMs and MFs was approximately 17...
January 23, 2018: Cell Death & Disease
Eleni Petsalaki, Maria Dandoulaki, George Zachos
The mitotic spindle checkpoint delays anaphase onset in the presence of unattached kinetochores, and efficient checkpoint signaling requires kinetochore localization of the Rod-ZW10-Zwilch (RZZ) complex. In the present study, we show that human Chmp4c, a protein involved in membrane remodeling, localizes to kinetochores in prometaphase but is reduced in chromosomes aligned at the metaphase plate. Chmp4c promotes stable kinetochore-microtubule attachments and is required for proper mitotic progression, faithful chromosome alignment, and segregation...
March 5, 2018: Journal of Cell Biology
Yajuan Lu, Sen Li, Zhaokang Cui, Xiaoxin Dai, Mianqun Zhang, Yilong Miao, Changyin Zhou, Xianghong Ou, Bo Xiong
Esco1 has been reported to function as a cohesion establishment factor that mediates chromosome cohesion and segregation in mitotic cells. However, its exact roles in meiosis have not been clearly defined. Here, we document that Esco1 is expressed and localized to both the nucleus and cytoplasm during mouse oocyte meiotic maturation. Depletion of Esco1 by siRNA microinjection causes the meiotic progression arrest with a severe spindle abnormality and chromosome misalignment, which is coupled with a higher incidence of the erroneous kinetochore-microtubule attachments and activation of spindle assembly checkpoint...
March 16, 2018: Nucleic Acids Research
Yang Yang, Xuan Zhang, Hongfei Ge, Wei Liu, Eryi Sun, Yuanyuan Ma, Hengli Zhao, Rongwei Li, Weixiang Chen, Jichao Yuan, Qianwei Chen, Yujie Chen, Xin Liu, John H Zhang, Rong Hu, Xiaotang Fan, Hua Feng
BACKGROUND: Many previous clinical studies have demonstrated that the nigrostriatal pathway, which plays a vital role in movement adjustment, is significantly impaired after stroke, according to medical imaging and autopsies. However, the basic pathomorphological changes have been poorly investigated to date. This study was designed to explore the pathomorphological changes, mechanism, and therapeutic method of nigrostriatal impairment after intracerebral hemorrhage (ICH). METHODS AND RESULTS: Intrastriatal injection of autologous blood or microtubule depolymerization reagent nocodazole was performed to mimic the pathology of ICH in C57/BL6 mice...
January 18, 2018: Journal of the American Heart Association
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