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https://www.readbyqxmd.com/read/29348204/tumor-suppressor-apc-is-an-attenuator-of-spindle-pulling-forces-during-c-elegans-asymmetric-cell-division
#1
Kenji Sugioka, Lars-Eric Fielmich, Kota Mizumoto, Bruce Bowerman, Sander van den Heuvel, Akatsuki Kimura, Hitoshi Sawa
The adenomatous polyposis coli (APC) tumor suppressor has dual functions in Wnt/β-catenin signaling and accurate chromosome segregation and is frequently mutated in colorectal cancers. Although APC contributes to proper cell division, the underlying mechanisms remain poorly understood. Here we show that Caenorhabditis elegans APR-1/APC is an attenuator of the pulling forces acting on the mitotic spindle. During asymmetric cell division of the C. elegans zygote, a LIN-5/NuMA protein complex localizes dynein to the cell cortex to generate pulling forces on astral microtubules that position the mitotic spindle...
January 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29348145/fbxl13-directs-the-proteolysis-of-cep192-to-regulate-centrosome-homeostasis-and-cell-migration
#2
Ella Fung, Carmen Richter, Hong-Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, Vincenzo D'Angiolella
Aberrant centrosome organisation with ensuing alterations of microtubule nucleation capacity enables tumour cells to proliferate and invade despite increased genomic instability. CEP192 is a key factor in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation. However, regulatory means of CEP192 have remained unknown. Here, we report that FBXL13, a binding determinant of SCF (SKP1-CUL1-F-box)-family E3 ubiquitin ligases, is enriched at centrosomes and interacts with the centrosomal proteins Centrin-2, Centrin-3, CEP152 and CEP192...
January 18, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29342242/meiotic-spindle-formation-in-mammalian-oocytes-implications-for-human-infertility
#3
Suk Namgoong, Nam-Hyung Kim
In the final stage of oogenesis, mammalian oocytes generate a meiotic spindle and undergo chromosome segregation to yield an egg that is ready for fertilization. Herein, we describe the recent advances in understanding the mechanisms controlling formation of the meiotic spindle in metaphase I (MI) and metaphase II (MII) in mammalian oocytes, and focus on the differences between mouse and human oocytes. Unlike mitotic cells, mammalian oocytes lack typical centrosomes that consist of two centrioles and the surrounding pericentriolar matrix proteins (PCM), which serve as microtubule-organizing centers (MTOCs) in most somatic cells...
January 12, 2018: Biology of Reproduction
https://www.readbyqxmd.com/read/29339437/spr2-protects-minus-ends-to-promote-severing-and-reorientation-of-plant-cortical-microtubule-arrays
#4
Masayoshi Nakamura, Jelmer J Lindeboom, Marco Saltini, Bela M Mulder, David W Ehrhardt
The cortical microtubule arrays of higher plants are organized without centrosomes and feature treadmilling polymers that are dynamic at both ends. The control of polymer end stability is fundamental for the assembly and organization of cytoskeletal arrays, yet relatively little is understood about how microtubule minus ends are controlled in acentrosomal microtubule arrays, and no factors have been identified that act at the treadmilling minus ends in higher plants. Here, we identify Arabidopsis thaliana SPIRAL2 (SPR2) as a protein that tracks minus ends and protects them against subunit loss...
January 16, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29330318/shifting-meiotic-to-mitotic-spindle-assembly-in-oocytes-disrupts-chromosome-alignment
#5
Isma Bennabi, Isabelle Quéguiner, Agnieszka Kolano, Thomas Boudier, Philippe Mailly, Marie-Hélène Verlhac, Marie-Emilie Terret
Mitotic spindles assemble from two centrosomes, which are major microtubule-organizing centers (MTOCs) that contain centrioles. Meiotic spindles in oocytes, however, lack centrioles. In mouse oocytes, spindle microtubules are nucleated from multiple acentriolar MTOCs that are sorted and clustered prior to completion of spindle assembly in an "inside-out" mechanism, ending with establishment of the poles. We used HSET (kinesin-14) as a tool to shift meiotic spindle assembly toward a mitotic "outside-in" mode and analyzed the consequences on the fidelity of the division...
January 12, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29330283/centriole-overduplication-is-the-predominant-mechanism-leading-to-centrosome-amplification-in-melanoma
#6
Ryan A Denu, Maria Shabbir, Minakshi Nihal, Chandra K Singh, B Jack Longley, Mark E Burkard, Nihal Ahmad
Centrosome amplification (CA) is common in cancer and can arise by centriole overduplication or by cell doubling events, including the failure of cell division and cell-cell fusion. To assess the relative contributions of these two mechanisms, the number of centrosomes with mature/mother centrioles was examined by immunofluorescence in a tissue microarray (TMA) of human melanomas and benign nevi (n=79 and 17, respectively). The centrosomal protein 170 (CEP170) was used to identify centrosomes with mature centrioles; this is expected to be present in most centrosomes with cell doubling, but on fewer centrosomes with overduplication...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29326161/sumo2-3-modification-of-activating-transcription-factor-5-atf5-controls-its-dynamic-translocation-at-the-centrosome
#7
Yunsheng Yuan, Kari Gaither, Eugene Kim, Edward Liu, Ming Hu, Kathy Lengel, Dongmeng Qian, Yidi Xu, Bin Wang, Henning Knipprath, David Liu
Activating transcription factor 5 (ATF5) is a member of the ATF/CREB family of transcription factors. ATF5 regulates stress responses and cell survival, proliferation, and differentiation and also plays a role in viral infections, cancer, diabetes, schizophrenia, and the olfactory system. Moreover, it was found to also have a critical, cell cycle-dependent structural function at the centrosome. However, the mechanism that controls ATF5's localization at the centrosome is unclear. Here, we report that ATF5 is SUMO2/3- modified at a conserved SUMO-targeting consensus site in various types of mammalian cells...
January 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29324869/exploring-the-binding-sites-and-binding-mechanism-for-hydrotrope-encapsulated-griseofulvin-drug-on-%C3%AE-tubulin-protein
#8
Shubhadip Das, Sandip Paul
The protein γ-tubulin plays an important role in centrosomal clustering and this makes it an attractive therapeutic target for treating cancers. Griseofulvin, an antifungal drug, has recently been used to inhibit proliferation of various types of cancer cells. It can also affect the microtubule dynamics by targeting the γ-tubulin protein. So far, the binding pockets of γ-tubulin protein are not properly identified and the exact mechanism by which the drug binds to it is an area of intense speculation and research...
2018: PloS One
https://www.readbyqxmd.com/read/29315319/the-centrosomin-cm2-domain-is-a-multi-functional-binding-domain-with-distinct-cell-cycle-roles
#9
Y Rose Citron, Carey J Fagerstrom, Bettina Keszthelyi, Bo Huang, Nasser M Rusan, Mark J S Kelly, David A Agard
The centrosome serves as the main microtubule-organizing center in metazoan cells, yet despite its functional importance, little is known mechanistically about the structure and organizational principles that dictate protein organization in the centrosome. In particular, the protein-protein interactions that allow for the massive structural transition between the tightly organized interphase centrosome and the highly expanded matrix-like arrangement of the mitotic centrosome have been largely uncharacterized...
2018: PloS One
https://www.readbyqxmd.com/read/29311228/tpxl-1-activates-aurora-a-to-clear-contractile-ring-components-from-the-polar-cortex-during-cytokinesis
#10
Sriyash Mangal, Jennifer Sacher, Taekyung Kim, Daniel Sampaio Osório, Fumio Motegi, Ana Xavier Carvalho, Karen Oegema, Esther Zanin
During cytokinesis, a signal from the central spindle that forms between the separating anaphase chromosomes promotes the accumulation of contractile ring components at the cell equator, while a signal from the centrosomal microtubule asters inhibits accumulation of contractile ring components at the cell poles. However, the molecular identity of the inhibitory signal has remained unknown. To identify molecular components of the aster-based inhibitory signal, we developed a means to monitor the removal of contractile ring proteins from the polar cortex after anaphase onset...
January 8, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29307730/zyg-1-promotes-limited-centriole-amplification-in-the-c-elegans-seam-lineage
#11
Benita Wolf, Fernando R Balestra, Antoine Spahr, Pierre Gönczy
Genome stability relies notably on the integrity of centrosomes and of the mitotic spindle they organize. Structural and numerical centrosome aberrations are frequently observed in human cancer, and there is increasing evidence that centrosome amplification can promote tumorigenesis. Here, we use C. elegans seam cells as a model system to analyze centrosome homeostasis in the context of a stereotyped stem like lineage. We found that overexpression of the Plk4-related kinase ZYG-1 leads to the formation of one supernumerary centriolar focus per parental centriole during the cell cycle that leads to the sole symmetric division in the seam lineage...
January 4, 2018: Developmental Biology
https://www.readbyqxmd.com/read/29301947/subcellular-specialization-and-organelle-behavior-in-germ-cells
#12
Yukiko M Yamashita
Gametes, eggs and sperm, are the highly specialized cell types on which the development of new life solely depends. Although all cells share essential organelles, such as the ER (endoplasmic reticulum), Golgi, mitochondria, and centrosomes, germ cells display unique regulation and behavior of organelles during gametogenesis. These germ cell-specific functions of organelles serve critical roles in successful gamete production. In this chapter, I will review the behaviors and roles of organelles during germ cell differentiation...
January 2018: Genetics
https://www.readbyqxmd.com/read/29298345/redox-modulation-of-nqo1
#13
David Siegel, Donna D Dehn, Samantha S Bokatzian, Kevin Quinn, Donald S Backos, Andrea Di Francesco, Michel Bernier, Nichole Reisdorph, Rafael de Cabo, David Ross
NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates. In cells, NQO1 participates in a number of binding interactions with other proteins and mRNA and these interactions may be influenced by the concentrations of reduced pyridine nucleotides. NAD(P)H can protect NQO1 from proteolytic digestion suggesting that binding of reduced pyridine nucleotides results in a change in NQO1 structure. We have used purified NQO1 to demonstrate the addition of NAD(P)H induces a change in the structure of NQO1; this results in the loss of immunoreactivity to antibodies that bind to the C-terminal domain and to helix 7 of the catalytic core domain...
2018: PloS One
https://www.readbyqxmd.com/read/29286416/immuno-fluorescent-labeling-of-microtubules-and-centrosomal-proteins-in-ex-vivo-intestinal-tissue-and-3d-in-vitro-intestinal-organoids
#14
Deborah A Goldspink, Zoe J Matthews, Elizabeth K Lund, Tom Wileman, Mette M Mogensen
The advent of 3D in vitro organoids that mimic the in vivo tissue architecture and morphogenesis has greatly advanced the ability to study key biological questions in cell and developmental biology. In addition, organoids together with recent technical advances in gene editing and viral gene delivery promises to advance medical research and development of new drugs for treatment of diseases. Organoids grown in vitro in basement matrix provide powerful model systems for studying the behavior and function of various proteins and are well suited for live-imaging of fluorescent-tagged proteins...
December 13, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29284667/building-the-right-centriole-for-each-cell-type
#15
REVIEW
Jadranka Loncarek, Mónica Bettencourt-Dias
The centriole is a multifunctional structure that organizes centrosomes and cilia and is important for cell signaling, cell cycle progression, polarity, and motility. Defects in centriole number and structure are associated with human diseases including cancer and ciliopathies. Discovery of the centriole dates back to the 19th century. However, recent advances in genetic and biochemical tools, development of high-resolution microscopy, and identification of centriole components have accelerated our understanding of its assembly, function, evolution, and its role in human disease...
December 28, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29283376/differential-selective-pressures-experienced-by-the-aurora-kinase-gene-family
#16
Joni M Seeling, Alexis A Farmer, Adam Mansfield, Hyuk Cho, Madhusudan Choudhary
Aurora kinases (AKs) are serine/threonine kinases that are essential for cell division. Humans have three AK genes: AKA, AKB, and AKC. AKA is required for centrosome assembly, centrosome separation, and bipolar spindle assembly, and its mutation leads to abnormal spindle morphology. AKB is required for the spindle checkpoint and proper cytokinesis, and mutations cause chromosome misalignment and cytokinesis failure. AKC is expressed in germ cells, and has a role in meiosis analogous to that of AKB in mitosis...
December 28, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29282278/gravin-regulates-centrosome-function-through-plk1
#17
Erica G Colicino, Alice M Garrastegui, Judy Freshour, Peu Santra, Dawn E Post, Leszek Kotula, Heidi Hehnly
Here we propose to understand how the mitotic kinase PLK1 drives chromosome segregation errors, with a specific focus on Gravin, a PLK1 scaffold. In both 3-D primary prostate cancer cell cultures that are prone to Gravin-depletion and Gravin shRNA treated cells, an increase in cells containing micronuclei was noted when compared to controls. To examine whether the loss of Gravin affected PLK1 distribution and activity we utilized photokinetics and a PLK1 activity-biosensor. Gravin-depletion resulted in an increased PLK1 mobile fraction, causing the redistribution of active-PLK1 that leads to increased defocusing and phosphorylation of the mitotic centrosome protein CEP215 at serine-613...
December 27, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29276125/nek9-phosphorylation-defines-a-new-role-for-tpx2-in-eg5-dependent-centrosome-separation-before-nuclear-envelope-breakdown
#18
Susana Eibes, Núria Gallisà-Suñé, Miquel Rosas-Salvans, Paula Martínez-Delgado, Isabelle Vernos, Joan Roig
Centrosomes [1, 2] play a central role during spindle assembly in most animal cells [3]. In early mitosis, they organize two symmetrical microtubule arrays that upon separation define the two poles of the forming spindle. Centrosome separation is tightly regulated [4, 5], occurring through partially redundant mechanisms that rely on the action of microtubule-based dynein and kinesin motors and the actomyosin system [6]. While centrosomes can separate in prophase or in prometaphase after nuclear envelope breakdown (NEBD), prophase centrosome separation optimizes spindle assembly and minimizes the occurrence of abnormal chromosome attachments that could end in aneuploidy [7, 8]...
December 13, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29259543/neural-progenitor-cell-polarity-and-cortical-development
#19
Yoko Arai, Elena Taverna
Neurons populating the cerebral cortex are generated during embryonic development from neural stem and progenitor cells in a process called neurogenesis. Neural stem and progenitor cells are classified into several classes based on the different location of mitosis (apical or basal) and polarity features (bipolar, monopolar and non-polar). The polarized architecture of stem cells is linked to the asymmetric localization of proteins, mRNAs and organelles, such as the centrosome and the Golgi apparatus (GA). Polarity affects stem cell function and allows stem cells to integrate environmental cues from distinct niches in the developing cerebral cortex...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29259156/dual-blockade-of-the-lipid-kinase-pip4ks-and-mitotic-pathways-leads-to-cancer-selective-lethality
#20
Mayumi Kitagawa, Pei-Ju Liao, Kyung Hee Lee, Jasmine Wong, See Cheng Shang, Noriaki Minami, Oltea Sampetrean, Hideyuki Saya, Dai Lingyun, Nayana Prabhu, Go Ka Diam, Radoslaw Sobota, Andreas Larsson, Pär Nordlund, Frank McCormick, Sujoy Ghosh, David M Epstein, Brian W Dymock, Sang Hyun Lee
Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway...
December 19, 2017: Nature Communications
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