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centrosome amplification

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https://www.readbyqxmd.com/read/27926524/selective-hdac-inhibition-by-acy-241-enhances-the-activity-of-paclitaxel-in-solid-tumor-models
#1
Pengyu Huang, Ingrid Almeciga-Pinto, Matthew Jarpe, John H van Duzer, Ralph Mazitschek, Min Yang, Simon S Jones, Steven N Quayle
ACY-241 is a novel, orally available and selective histone deacetylase (HDAC) 6 inhibitor in Phase 1b clinical development in multiple myeloma (NCT 02400242). Like the structurally related drug ACY-1215 (ricolinostat), ACY-241 has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor drug candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness. We now show that combination treatment of xenograft models with paclitaxel and either ricolinostat or ACY-241 significantly suppresses solid tumor growth...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27924065/the-more-the-messier-centrosome-amplification-as-a-novel-biomarker-for-personalized-treatment-of-colorectal-cancers
#2
REVIEW
Monica M Mahathre, Padmashree Cg Rida, Ritu Aneja
Colon cancer is currently the third most common cancer and second most fatal cancer in the United States, resulting in approximately 600,000 deaths annually. Though colorectal cancer death rates are decreasing by about 3% every year, disease outcomes could be substantially improved with more research into the drivers of colon carcinogenesis, the determinants of aggressiveness in colorectal cancer and the identification of biomarkers that could enable choice of more optimal treatments. Colon carcinogenesis is notably a slow process that can take decades...
November 2016: Journal of Biomedical Research
https://www.readbyqxmd.com/read/27911707/the-plk4-stil-sas-6-module-at-the-core-of-centriole-duplication
#3
REVIEW
Christian Arquint, Erich A Nigg
Centrioles are microtubule-based core components of centrosomes and cilia. They are duplicated exactly once during S-phase progression. Central to formation of each new (daughter) centriole is the formation of a nine-fold symmetrical cartwheel structure onto which microtubule triplets are deposited. In recent years, a module comprising the protein kinase polo-like kinase 4 (PLK4) and the two proteins STIL and SAS-6 have been shown to stay at the core of centriole duplication. Depletion of any one of these three proteins blocks centriole duplication and, conversely, overexpression causes centriole amplification...
October 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27872092/plk4-promotes-cancer-invasion-and-metastasis-through-arp2-3-complex-regulation-of-the-actin-cytoskeleton
#4
Karineh Kazazian, Christopher D Go, Hannah Wu, Olga Brashavitskaya, Roland S Z Xu, James W Dennis, Anne-Claude Gingras, Carol Swallow
The polo family serine threonine kinase Plk4 has been proposed as a therapeutic target in advanced cancers based on increased expression in primary human cancers, facilitation of tumor growth in murine xenograft models, and centrosomal amplification induced by its overexpression. However, both the causal link between these phenomena and the feasibility of selective Plk4 inhibition remain unclear. Here we characterize Plk4-dependent cancer cell migration and invasion as well as local invasion and metastasis of cancer xenografts...
November 21, 2016: Cancer Research
https://www.readbyqxmd.com/read/27796307/kat2a-kat2b-targeted-acetylome-reveals-a-role-for-plk4-acetylation-in-preventing-centrosome-amplification
#5
Marjorie Fournier, Meritxell Orpinell, Cédric Grauffel, Elisabeth Scheer, Jean-Marie Garnier, Tao Ye, Virginie Chavant, Mathilde Joint, Fumiko Esashi, Annick Dejaegere, Pierre Gönczy, László Tora
Lysine acetylation is a widespread post-translational modification regulating various biological processes. To characterize cellular functions of the human lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), we determined their acetylome by shotgun proteomics. One of the newly identified KAT2A/2B substrate is polo-like kinase 4 (PLK4), a key regulator of centrosome duplication. We demonstrate that KAT2A/2B acetylate the PLK4 kinase domain on residues K45 and K46. Molecular dynamics modelling suggests that K45/K46 acetylation impairs kinase activity by shifting the kinase to an inactive conformation...
October 31, 2016: Nature Communications
https://www.readbyqxmd.com/read/27693136/centrosome-amplification-increases-single-cell-branching-in-post-mitotic-cells
#6
Delia Ricolo, Myrto Deligiannaki, Jordi Casanova, Sofia J Araújo
Centrosome amplification is a hallmark of cancer, although we are still far from understanding how this process affects tumorigenesis [1, 2]. Besides the contribution of supernumerary centrosomes to mitotic defects, their biological effects in the post-mitotic cell are not well known. Here, we exploit the effects of centrosome amplification in post-mitotic cells during single-cell branching. We show that Drosophila tracheal cells with extra centrosomes branch more than wild-type cells. We found that mutations in Rca1 and CycA affect subcellular branching, causing tracheal tip cells to form more than one subcellular lumen...
September 17, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/27634760/pharmacological-inhibition-of-centrosome-clustering-by-slingshot-mediated-cofilin-activation-and-actin-cortex-destabilization
#7
Gleb Konotop, Elena Bausch, Tomoaki Nagai, Andrey Turchinovich, Natalia Becker, Axel Benner, Michael Boutros, Kensaku Mizuno, Alwin Krämer, Marc S Raab
Centrosome amplification (CA) is a hallmark of virtually all types of cancers including solid tumors and hematological malignancies. Cancer cells with extra centrosomes use centrosome clustering (CC) to allow for successful division. Because normal cells do not rely on this mechanism, CC is regarded as a promising target to selectively eradicate cells harboring supernumerary centrosomes. To identify novel inhibitors of CC, we developed a cell-based high-throughput screen that reports differential drug cytotoxicity for isogenic cell populations with different centrosome contents...
September 13, 2016: Cancer Research
https://www.readbyqxmd.com/read/27621083/the-centrosomal-deubiquitylase-usp21-regulates-gli1-transcriptional-activity-and-stability
#8
Claire Heride, Daniel J Rigden, Erithelgi Bertsoulaki, Danilo Cucchi, Enrico De Smaele, Michael J Clague, Sylvie Urbé
USP21 is a centrosome-associated deubiquitylase (DUB) that has been implicated in the formation of primary cilia - crucial organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here, we identify KCTD6 - a cullin-3 E3-ligase substrate adapter that has been previously linked to Hh signaling - as well as Gli1, the key transcription factor responsible for Hh signal amplification, as new interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to have a similar fold to Smr domains...
November 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27592797/an-interaction-between-arsenic-induced-epigenetic-modification-and-inflammatory-promotion-in-a-skin-equivalent-during-arsenic-carcinogenesis
#9
Wei-Ting Liao, Jian-He Lu, Chih-Hung Lee, Cheng-Che E Lan, Jan-Gowth Chang, Chee-Yin Chai, Hsin-Su Yu
Animal studies have shown that chemical carcinogenesis consists of a three-stage process: initiation, promotion, and progression. However, because of the lack of a suitable tissue model, the molecular mechanisms of cell-cell interactions involved in those processes remain unclear. We have established a human intraepidermal carcinoma skin equivalent with organotypic culture-consisting of keratinocytes, fibroblasts, and peripheral blood mononuclear cells - induced by arsenic treatment. This SE shows the pathognomonic characteristics of arsenic-induced Bowen's disease, including acanthosis, dysplasia, and dyskeratosis...
September 1, 2016: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/27544453/t0070907-inhibits-repair-of-radiation-induced-dna-damage-by-targeting-rad51
#10
Zhengzhe An, Jae-Ran Yu, Woo-Yoon Park
T0070907 (T007), a PPARγ inhibitor, can reduce α and β tubulin proteins in some cancer cell lines. Thus, T007 has been suggested as an antimicrotubule drug. We previously reported that T007 increased radiosensitivity by inducing mitotic catastrophe in cervical cancer cells. In this study, we investigated the underlying mechanisms of the T007-mediated increase in radiosensitivity. T007 pre-treatment attenuated RAD51 protein levels and ionising radiation (IR)-induced nuclear foci formation, resulting in more frequent centrosome amplification and multipolar mitotic spindle formation in cervical cancer cells...
December 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/27443516/ccne1-amplification-and-centrosome-number-abnormality-in-serous-tubal-intraepithelial-carcinoma-further-evidence-supporting-its-role-as-a-precursor-of-ovarian-high-grade-serous-carcinoma
#11
Elisabetta Kuhn, Tian-Li Wang, Kai Doberstein, Asli Bahadirli-Talbott, Ayse Ayhan, Ann Smith Sehdev, Ronny Drapkin, Robert J Kurman, Ie-Ming Shih
Aberration in chromosomal structure characterizes almost all cancers and has profound biological significance in tumor development. It can be facilitated by various mechanisms including overexpression of cyclin E1 and centrosome amplification. As ovarian high-grade serous carcinoma has pronounced chromosomal instability, in this study we sought to determine whether increased copy number of CCNE1 which encodes cyclin E1 and centrosome amplification (>2 copies) occurs in its putative precursor, serous tubal intraepithelial carcinoma...
October 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27388476/epigenetic-silencing-of-serine-protease-htra1-drives-polyploidy
#12
Nina Schmidt, Inga Irle, Kamilla Ripkens, Vanda Lux, Jasmin Nelles, Christian Johannes, Lee Parry, Kirsty Greenow, Sarah Amir, Mara Campioni, Alfonso Baldi, Chio Oka, Masashi Kawaichi, Alan R Clarke, Michael Ehrmann
BACKGROUND: Increased numbers and improperly positioned centrosomes, aneuploidy or polyploidy, and chromosomal instability are frequently observed characteristics of cancer cells. While some aspects of these events and the checkpoint mechanisms are well studied, not all players have yet been identified. As the role of proteases other than the proteasome in tumorigenesis is an insufficiently addressed question, we investigated the epigenetic control of the widely conserved protease HTRA1 and the phenotypes of deregulation...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27253419/14-3-3%C3%AE-prevents-centrosome-amplification-and-neoplastic-progression
#13
Amitabha Mukhopadhyay, Lalit Sehgal, Arunabha Bose, Anushree Gulvady, Parijat Senapati, Rahul Thorat, Srikanta Basu, Khyati Bhatt, Amol S Hosing, Renu Balyan, Lalit Borde, Tapas K Kundu, Sorab N Dalal
More than 80% of malignant tumors show centrosome amplification and clustering. Centrosome amplification results from aberrations in the centrosome duplication cycle, which is strictly coordinated with DNA-replication-cycle. However, the relationship between cell-cycle regulators and centrosome duplicating factors is not well understood. This report demonstrates that 14-3-3γ localizes to the centrosome and 14-3-3γ loss leads to centrosome amplification. Loss of 14-3-3γ results in the phosphorylation of NPM1 at Thr-199, causing early centriole disjunction and centrosome hyper-duplication...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27245623/gastric-cancer-patients-with-high-plk1-expression-and-dna-aneuploidy-correlate-with-poor-prognosis
#14
Hajime Otsu, Makoto Iimori, Koji Ando, Hiroshi Saeki, Shinichi Aishima, Yoshinao Oda, Masaru Morita, Keitaro Matsuo, Hiroyuki Kitao, Eiji Oki, Yoshihiko Maehara
Gastric cancer is the fourth most common cancer worldwide. Although it is important to identify patients at high risk for a poor outcome, factors correlating with prognosis in gastric cancer are largely unknown. Here, we focus on the correlations among expression of Polo-like kinase 1 (PLK1), DNA ploidy, and clinical outcome in gastric cancer patients. Gastric cancer specimens were analyzed from 207 consecutive patients. Patients were classified into two groups according to tumor PLK1 expression and DNA content, and an analysis of their clinical outcomes was carried out...
2016: Oncology
https://www.readbyqxmd.com/read/27197215/large-scale-analysis-of-genome-and-transcriptome-alterations-in-multiple-tumors-unveils-novel-cancer-relevant-splicing-networks
#15
Endre Sebestyén, Babita Singh, Belén Miñana, Amadís Pagès, Francesca Mateo, Miguel Angel Pujana, Juan Valcárcel, Eduardo Eyras
Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. We systematically analyzed mutation, copy number, and gene expression patterns of 1348 RNA-binding protein (RBP) genes in 11 solid tumor types, together with alternative splicing changes in these tumors and the enrichment of binding motifs in the alternatively spliced sequences...
June 2016: Genome Research
https://www.readbyqxmd.com/read/27193861/using-cell-culture-models-of-centrosome-amplification-to-study-centrosome-clustering-in-cancer
#16
Mijung Kwon
The link between centrosome amplification and cancer has been recognized for more than a century, raising many key questions about the biology of both normal and cancer cells. In particular, the presence of extra centrosomes imposes a great challenge to a dividing cell by increasing the likelihood of catastrophic multipolar divisions. Only recently have we begun to understand how cancer cells successfully divide by clustering their extra centrosomes for bipolar division. Several hurdles to dissecting centrosome clustering include limitations in the methodologies used to quantify centrosome amplification, and the lack of appropriate cell culture models...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27121062/myosins-as-fundamental-components-during-tumorigenesis-diverse-and-indispensable
#17
Yan-Ruide Li, Wan-Xi Yang
Myosin is a kind of actin-based motor protein. As the crucial functions of myosin during tumorigenesis have become increasingly apparent, the profile of myosin in the field of cancer research has also been growing. Eighteen distinct classes of myosins have been discovered in the past twenty years and constitute a diverse superfamily. Various myosins share similar structures. They all convert energy from ATP hydrolysis to exert mechanical stress upon interactions with microfilaments. Ongoing research is increasingly suggesting that at least seven kinds of myosins participate in the formation and development of cancer...
April 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27065328/opposing-post-translational-modifications-regulate-cep76-function-to-suppress-centriole-amplification
#18
M Barbelanne, A Chiu, J Qian, W Y Tsang
Centrioles are critical for many cellular processes including cell division and cilia assembly. The number of centrioles within a cell is under strict control, and deregulation of centriole copy number is a hallmark of cancer. The molecular mechanisms that halt centriole amplification have not been fully elucidated. Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase...
October 13, 2016: Oncogene
https://www.readbyqxmd.com/read/26992853/a-centrosome-clustering-protein-kifc1-predicts-aggressive-disease-course-in-serous-ovarian-adenocarcinomas
#19
Karuna Mittal, Da Hoon Choi, Sergey Klimov, Shrikant Pawar, Ramneet Kaur, Anirban K Mitra, Meenakshi V Gupta, Ralph Sams, Guilherme Cantuaria, Padmashree C G Rida, Ritu Aneja
BACKGROUND: Amplified centrosomes are widely recognized as a hallmark of cancer. Although supernumerary centrosomes would be expected to compromise cell viability by yielding multipolar spindles that results in death-inducing aneuploidy, cancer cells suppress multipolarity by clustering their extra centrosomes. Thus, cancer cells, with the aid of clustering mechanisms, maintain pseudobipolar spindle phenotypes that are associated with low-grade aneuploidy, an edge to their survival. KIFC1, a nonessential minus end-directed motor of the kinesin-14 family, is a centrosome clustering molecule, essential for viability of extra centrosome-bearing cancer cells...
March 18, 2016: Journal of Ovarian Research
https://www.readbyqxmd.com/read/26987684/a-cep215-hset-complex-links-centrosomes-with-spindle-poles-and-drives-centrosome-clustering-in-cancer
#20
Pavithra L Chavali, Gayathri Chandrasekaran, Alexis R Barr, Péter Tátrai, Chris Taylor, Evaggelia K Papachristou, C Geoffrey Woods, Sreenivas Chavali, Fanni Gergely
Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer. A cell maintains normal centrosome numbers by coupling centrosome duplication with segregation, which is achieved through sustained association of each centrosome with a mitotic spindle pole. Although the microcephaly- and primordial dwarfism-linked centrosomal protein CEP215 has been implicated in this process, the molecular mechanism responsible remains unclear. Here, using proteomic profiling, we identify the minus end-directed microtubule motor protein HSET as a direct binding partner of CEP215...
March 18, 2016: Nature Communications
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