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centrosome amplification

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
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
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, critical organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here we identify KCTD6, a Cullin3 E3-ligase substrate adapter previously linked to Hh-signaling, as well as Gli1, the key transcription factor responsible for Hh signal amplification, as novel interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to bear fold similarity to Smr domains...
September 12, 2016: Journal of Cell Science
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
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
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
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
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
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
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
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
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
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...
April 11, 2016: Oncogene
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...
2016: Journal of Ovarian Research
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...
2016: Nature Communications
Irene V Bijnsdorp, Jasmina Hodzic, Tonny Lagerweij, Bart Westerman, Oscar Krijgsman, Jurjen Broeke, Frederik Verweij, R Jonas A Nilsson, Lawrence Rozendaal, Victor W van Beusechem, Jeroen A van Moorselaar, Thomas Wurdinger, Albert A Geldof
The centrosome plays a key role in cancer invasion and metastasis. However, it is unclear how abnormal centrosome numbers are regulated when prostate cancer (PCa) cells become metastatic. CP110 was previously described for its contribution of centrosome amplification (CA) and early development of aggressive cell behaviour. However its regulation in metastatic cells remains unclear. Here we identified miR-129-3p as a novel metastatic microRNA. CP110 was identified as its target protein. In PCa cells that have metastatic capacity, CP110 expression was repressed by miR-129-3p...
March 29, 2016: Oncotarget
Ryan A Denu, Lauren M Zasadil, Craig Kanugh, Jennifer Laffin, Beth A Weaver, Mark E Burkard
BACKGROUND: Centrosome amplification (CA) has been reported in nearly all types of human cancer and is associated with deleterious clinical factors such as higher grade and stage. However, previous reports have not shown how CA affects cellular differentiation and clinical outcomes in breast cancer. METHODS: We analyzed centrosomes by immunofluorescence and compared to ploidy and chromosomal instability (CIN) as assessed by 6-chromosome FISH in a cohort of 362 breast cancers with median clinical follow-up of 8...
2016: BMC Cancer
Jin Ki Jung, Seok-Won Jang, Jung Min Kim
Defects in the regulation of centrosome duplication lead to tumorigenesis through abnormal cell division and resulting chromosome missegregation. Therefore, maintenance of accurate centrosome number is critical for cell fate. The deubiquitinating enzyme USP1 plays important roles in DNA repair and cell differentiation. Importantly, increased levels of USP1 are detected in certain types of human cancer, but little is known about the significance of USP1 overexpression in cancer development. Here we show that Usp1 plays a novel role in regulating centrosome duplication...
2016: Cell Cycle
M Tumiati, P M Munne, H Edgren, S Eldfors, A Hemmes, S G Kuznetsov
Almost half of all hereditary breast cancers (BCs) are associated with germ-line mutations in homologous recombination (HR) genes. However, the tumor phenotypes associated with different HR genes vary, making it difficult to define the role of HR in BC predisposition. To distinguish between HR-dependent and -independent features of BCs, we generated a mouse model in which an essential HR gene, Rad51c, is knocked-out specifically in epidermal tissues. Rad51c is one of the key mediators of HR and a well-known BC predisposition gene...
September 1, 2016: Oncogene
Beatriz Araujo Cortez, Paula Rezende-Teixeira, Sambra Redick, Stephen Doxsey, Glaucia Maria Machado-Santelli
Chrysotile, like other types of asbestos, has been associated with mesothelioma, lung cancer and asbestosis. However, the cellular abnormalities induced by these fibers involved in cancer development have not been elucidated yet. Previous works show that chrysotile fibers induce features of cancer cells, such as aneuploidy, multinucleation and multipolar mitosis. In the present study, normal and cancer derived human cell lines were treated with chrysotile and the cellular and molecular mechanisms related to generation of aneuploid cells was elucidated...
February 23, 2016: Oncotarget
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