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https://www.readbyqxmd.com/read/28319064/oct4-controls-mitotic-stability-and-inactivates-the-rb-tumor-suppressor-pathway-to-enhance-ovarian-cancer-aggressiveness
#1
E Comisso, M Scarola, M Rosso, S Piazza, S Marzinotto, Y Ciani, M Orsaria, L Mariuzzi, C Schneider, S Schoeftner, R Benetti
OCT4 (Octamer-binding transcription factor 4) is essential for embryonic stem cell self-renewal. Here we show that OCT4 increases the aggressiveness of high-grade serous ovarian cancer (HG-SOC) by inactivating the Retinoblastoma tumor suppressor pathway and enhancing mitotic stability in cancer cells. OCT4 drives the expression of Nuclear Inhibitor of Protein Phosphatase type 1 (NIPP1) and Cyclin F (CCNF) that together inhibit Protein Phosphatase 1 (PP1). This results in pRB hyper-phosphorylation, accelerated cell proliferation and increased in vitro tumorigenicity of ovarian cancer cells...
March 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28299790/tc-mps1-12-a-novel-mps1-inhibitor-suppresses-a-growth-of-hepatocellular-carcinoma-cells-via-accumulated-chromosomal-instability
#2
Minji Choi, Yoo Hong Min, Jaehyuk Pyo, Chang-Woo Lee, Chang-Young Jang, Ja-Eun Kim
BACKGROUND AND PURPOSE: Chromosomal instability is not only a hallmark of cancer, but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed...
March 15, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28295209/a-nonsense-mutation-in-cep55-defines-a-new-locus-for-a-meckel-like-syndrome-an-autosomal-recessive-lethal-fetal-ciliopathy
#3
Marie-Louise Bondeson, Katharina Ericson, Sanna Gudmundsson, Adam Ameur, Fredrik Pontén, Jan Wesström, Carina Frykholm, Maria Wilbe
Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses...
March 14, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28292899/fission-yeast-myosin-i-facilitates-pi-4-5-p2-mediated-anchoring-of-cytoplasmic-dynein-to-the-cortex
#4
Jerrin Mathew Thankachan, Stephen Sukumar Nuthalapati, Nireekshit Addanki Tirumala, Vaishnavi Ananthanarayanan
Several key processes in the cell, such as vesicle transport and spindle positioning, are mediated by the motor protein cytoplasmic dynein, which produces force on the microtubule. For the functions that require movement of the centrosome and the associated nuclear material, dynein needs to have a stable attachment at the cell cortex. In fission yeast, Mcp5 is the anchor protein of dynein and is required for the oscillations of the horsetail nucleus during meiotic prophase. Although the role of Mcp5 in anchoring dynein to the cortex has been identified, it is unknown how Mcp5 associates with the membrane as well as the importance of the underlying attachment to the nuclear oscillations...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28289185/fifteen-years-of-research-on-oral-facial-digital-syndromes-from-1-to-16-causal-genes
#5
REVIEW
Ange-Line Bruel, Brunella Franco, Yannis Duffourd, Julien Thevenon, Laurence Jego, Estelle Lopez, Jean-François Deleuze, Diane Doummar, Rachel H Giles, Colin A Johnson, Martijn A Huynen, Véronique Chevrier, Lydie Burglen, Manuela Morleo, Isabelle Desguerres, Geneviève Pierquin, Bérénice Doray, Brigitte Gilbert-Dussardier, Bruno Reversade, Elisabeth Steichen-Gersdorf, Clarisse Baumann, Inusha Panigrahi, Anne Fargeot-Espaliat, Anne Dieux, Albert David, Alice Goldenberg, Ernie Bongers, Dominique Gaillard, Jesús Argente, Bernard Aral, Nadège Gigot, Judith St-Onge, Daniel Birnbaum, Shubha R Phadke, Valérie Cormier-Daire, Thibaut Eguether, Gregory J Pazour, Vicente Herranz-Pérez, Jaclyn S Goldstein, Laurent Pasquier, Philippe Loget, Sophie Saunier, André Mégarbané, Olivier Rosnet, Michel R Leroux, John B Wallingford, Oliver E Blacque, Maxence V Nachury, Tania Attie-Bitach, Jean-Baptiste Rivière, Laurence Faivre, Christel Thauvin-Robinet
Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS...
March 13, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28289130/inhibition-of-ectopic-microtubule-assembly-by-the-kinesin-13-klp-7-mcak-prevents-chromosome-segregation-and-cytokinesis-defects-in-oocytes
#6
Emmanuelle Gigant, Marine Stefanutti, Kimberley Laband, Agata Gluszek-Kustusz, Frances Edwards, Benjamin Lacroix, Gilliane Maton, Julie C Canman, Julie P I Welburn, Julien Dumont
In most species, oocytes lack centrosomes. Accurate meiotic spindle assembly and chromosome segregation -essential to prevent miscarriage or developmental defects- thus occur through atypical mechanisms that are not well characterized. Using quantitative in vitro and in vivo functional assays in the C. elegans oocyte, we provide here novel evidence that the kinesin-13 KLP-7 promotes the destabilization of the whole cellular microtubule network. By counteracting ectopic microtubule assembly and disorganization of the microtubule network, this function is strictly required for spindle organization, chromosome segregation, and cytokinesis in meiotic cells...
March 13, 2017: Development
https://www.readbyqxmd.com/read/28285824/clasp2-links-reelin-to-the-cytoskeleton-during-neocortical-development
#7
Gregory M Dillon, William A Tyler, Kerilyn C Omuro, John Kambouris, Camila Tyminski, Shawna Henry, Tarik F Haydar, Uwe Beffert, Angela Ho
The Reelin signaling pathway plays a crucial role in regulating neocortical development. However, little is known about how Reelin controls the cytoskeleton during neuronal migration. Here, we identify CLASP2 as a key cytoskeletal effector in the Reelin signaling pathway. We demonstrate that CLASP2 has distinct roles during neocortical development regulating neuron production and controlling neuron migration, polarity, and morphogenesis. We found downregulation of CLASP2 in migrating neurons leads to mislocalized cells in deeper cortical layers, abnormal positioning of the centrosome-Golgi complex, and aberrant length/orientation of the leading process...
March 8, 2017: Neuron
https://www.readbyqxmd.com/read/28284839/depletion-of-tumor-suppressor-kank1-induces-centrosomal-amplification-via-hyperactivation-of-rhoa
#8
Jun-Ichiro Suzuki, Badal Chandra Roy, Takunori Ogaeri, Naoto Kakinuma, Ryoiti Kiyama
Chromosome instability, frequently found in cancer cells, is caused by a deficiency in cell division, including centrosomal amplification and cytokinesis failure, and can result in abnormal chromosome content or aneuploidy. The small GTPase pathways have been implicated as important processes in cell division. We found that knockdown of a tumor suppressor protein Kank1 increases the number of cells with a micronucleus or bi-/multi-nuclei, which was likely caused by centrosomal amplification. Kank1 interacts with Daam1, known to bind to and activate a small GTPase, RhoA, in actin assembly...
March 8, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28277612/wdr62-overexpression-is-associated-with-a-poor-prognosis-in-patients-with-lung-adenocarcinoma
#9
Kazuya Shinmura, Hisami Kato, Yuichi Kawanishi, Hisaki Igarashi, Yusuke Inoue, Katsuhiro Yoshimura, Satoki Nakamura, Hidehiko Fujita, Kazuhito Funai, Masayuki Tanahashi, Hiroshi Niwa, Hiroshi Ogawa, Haruhiko Sugimura
Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.0432, Wilcoxon matched pairs test)...
March 9, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28272508/amplified-centrosomes-and-mitotic-index-display-poor-concordance-between-patient-tumors-and-cultured-cancer-cells
#10
Karuna Mittal, Da Hoon Choi, Angela Ogden, Shashi Donthamsetty, Brian D Melton, Meenakshi V Gupta, Vaishali Pannu, Guilherme Cantuaria, Sooryanarayana Varambally, Michelle D Reid, Kristin Jonsdottir, Emiel A M Janssen, Mohammad A Aleskandarany, Ian O Ellis, Emad A Rakha, Padmashree C G Rida, Ritu Aneja
Centrosome aberrations (CA) and abnormal mitoses are considered beacons of malignancy. Cancer cell doubling times in patient tumors are longer than in cultures, but differences in CA between tumors and cultured cells are uncharacterized. We compare mitoses and CA in patient tumors, xenografts, and tumor cell lines. We find that mitoses are rare in patient tumors compared with xenografts and cell lines. Contrastingly, CA is more extensive in patient tumors and xenografts (~35-50% cells) than cell lines (~5-15%), although CA declines in patient-derived tumor cells over time...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28272472/disruptions-in-asymmetric-centrosome-inheritance-and-wdr62-aurora-kinase-b-interactions-in-primary-microcephaly
#11
Paraskevi Sgourdou, Ketu Mishra-Gorur, Ichiko Saotome, Octavian Henagariu, Beyhan Tuysuz, Cynthia Campos, Keiko Ishigame, Krinio Giannikou, Jennifer L Quon, Nenad Sestan, Ahmet O Caglayan, Murat Gunel, Angeliki Louvi
Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28266547/the-molecular-motor-myosin-va-interacts-with-the-cilia-centrosomal-protein-rpgrip1l
#12
L H P Assis, R M P Silva-Junior, L G Dolce, M R Alborghetti, R V Honorato, A F Z Nascimento, T D Melo-Hanchuk, D M Trindade, C C C Tonoli, C T Santos, P S L Oliveira, R E Larson, J Kobarg, E M Espreafico, P O Giuseppe, M T Murakami
Myosin Va (MyoVa) is an actin-based molecular motor abundantly found at the centrosome. However, the role of MyoVa at this organelle has been elusive due to the lack of evidence on interacting partners or functional data. Herein, we combined yeast two-hybrid screen, biochemical studies and cellular assays to demonstrate that MyoVa interacts with RPGRIP1L, a cilia-centrosomal protein that controls ciliary signaling and positioning. MyoVa binds to the C2 domains of RPGRIP1L via residues located near or in the Rab11a-binding site, a conserved site in the globular tail domain (GTD) from class V myosins...
March 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28264986/a-truncating-mutation-in-cep55-is-the-likely-cause-of-march-a-novel-syndrome-affecting-neuronal-mitosis
#13
Patrick Frosk, Heleen H Arts, Julien Philippe, Carter S Gunn, Emma L Brown, Bernard Chodirker, Louise Simard, Jacek Majewski, Somayyeh Fahiminiya, Chad Russell, Yangfan P Liu, Robert Hegele, Nicholas Katsanis, Conrad Goerz, Marc R Del Bigio, Erica E Davis
BACKGROUND: Hydranencephaly is a congenital anomaly leading to replacement of the cerebral hemispheres with a fluid-filled cyst. The goals of this work are to describe a novel autosomal-recessive syndrome that includes hydranencephaly (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly (MARCH)); to identify its genetic cause(s) and to provide functional insight into pathomechanism. METHODS: We used homozygosity mapping and exome sequencing to identify recessive mutations in a single family with three affected fetuses...
March 6, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28264000/evaluation-of-rint1-as-a-modifier-of-intestinal-tumorigenesis-and-cancer-risk
#14
Karla L Otterpohl, Karen A Gould
The Rad50 Interacting Protein 1 (Rint1) influences cellular homeostasis through maintenance of endoplasmic reticulum, Golgi and centrosome integrity and regulation of vesicle transport, autophagy and the G2/M checkpoint. Rint1 has been postulated to function as a tumor suppressor as well as an oncogene, with its role depending perhaps upon the precise cellular and/or experimental context. In humans, heterozygosity for germline missense variants in RINT1 have, in some studies, been associated with increased risk of both breast and Lynch syndrome type cancers...
2017: PloS One
https://www.readbyqxmd.com/read/28263957/the-tetrameric-kinesin-kif25-suppresses-pre-mitotic-centrosome-separation-to-establish-proper-spindle%C3%A2-orientation
#15
Justin Decarreau, Michael Wagenbach, Eric Lynch, Aaron R Halpern, Joshua C Vaughan, Justin Kollman, Linda Wordeman
Microtubules tether centrosomes together during interphase. How this is accomplished and what benefit it provides to the cell is not known. We have identified a bipolar, minus-end-directed kinesin, Kif25, that suppresses centrosome separation. Kif25 is required to prevent premature centrosome separation during interphase. We show that premature centrosome separation leads to microtubule-dependent nuclear translocation, culminating in eccentric nuclear positioning that disrupts the cortical spindle positioning machinery...
March 6, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28263324/cryo-em-structure-of-a-metazoan-separase-securin-complex-at-near-atomic-resolution
#16
Andreas Boland, Thomas G Martin, Ziguo Zhang, Jing Yang, Xiao-Chen Bai, Leifu Chang, Sjors H W Scheres, David Barford
Separase is a caspase-family protease that initiates chromatid segregation by cleaving the kleisin subunits (Scc1 and Rec8) of cohesin, and regulates centrosome duplication and mitotic spindle function through cleavage of kendrin and Slk19. To understand the mechanisms of securin regulation of separase, we used single-particle cryo-electron microscopy (cryo-EM) to determine a near-atomic-resolution structure of the Caenorhabditis elegans separase-securin complex. Separase adopts a triangular-shaped bilobal architecture comprising an N-terminal tetratricopeptide repeat (TPR)-like α-solenoid domain docked onto the conserved C-terminal protease domain...
March 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28259529/novel-pyrrolopyrimidines-as-mps1-ttk-kinase-inhibitors-for-breast-cancer
#17
Yasuro Sugimoto, Dwitiya B Sawant, Harold A Fisk, Liguang Mao, Chenglong Li, Somsundaram Chettiar, Pui-Kai Li, Michael V Darby, Robert W Brueggemeier
New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions...
February 16, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28258034/synthesis-and-formulation-studies-of-griseofulvin-analogues-with-improved-solubility-and-metabolic-stability
#18
Asger B Petersen, Nikolaj S Andersen, Gleb Konotop, Nur Hafzan Md Hanafiah, Marc S Raab, Alwin Krämer, Mads H Clausen
Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility...
April 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28255694/analysis-of-microtubules-and-microtubule-organizing-center-at-the-immune-synapse
#19
Noelia Blas-Rus, Eugenio Bustos-Morán, Francisco Sánchez-Madrid, Noa B Martín-Cófreces
The immune synapse (IS) is a specialized structure that enables cell-cell communication between immune cells. As such, it involves direct cell-to-cell contact. It is sustained by cytoskeletal components that allow the intracellular polarization of different organelles and the surface re-organization of signaling and adhesion receptors. The tubulin-based cytoskeleton is a key player in IS formation and signaling. We describe methods to analyze through Western blot and microscopy analysis the polarization to the IS of the centrosome, also known as microtubule-organizing center (MTOC), the dynamics of microtubule growth and polymerization from the MTOC to the IS and the activation of signaling molecules...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28245431/lesion-complexity-drives-age-related-cancer-susceptibility-in-human-mammary-epithelial-cells
#20
Deepa M Sridharan, Shiena Enerio, Janice M Pluth
Exposures to various DNA damaging agents can deregulate a wide array of critical mechanisms that maintain genome integrity. It is unclear how these processes are impacted by one's age at the time of exposure and the complexity of the DNA lesion. To clarify this, we employed radiation as a tool to generate simple and complex lesions in normal primary human mammary epithelial cells derived from women of various ages. We hypothesized that genomic instability in the progeny of older cells exposed to complex damages will be exacerbated by age-associated deterioration in function and accentuate age-related cancer predisposition...
February 28, 2017: Aging
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