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https://www.readbyqxmd.com/read/28091594/functional-analysis-reveals-that-rbm10-mutations-contribute-to-lung-adenocarcinoma-pathogenesis-by-deregulating-splicing
#1
Jiawei Zhao, Yue Sun, Yin Huang, Fan Song, Zengshu Huang, Yufang Bao, Ji Zuo, David Saffen, Zhen Shao, Wen Liu, Yongbo Wang
RBM10 is an RNA splicing regulator that is frequently mutated in lung adenocarcinoma (LUAD) and has recently been proposed to be a cancer gene. How RBM10 mutations observed in LUAD affect its normal functions, however, remains largely unknown. Here integrative analysis of RBM10 mutation and RNA expression data revealed that LUAD-associated RBM10 mutations exhibit a mutational spectrum similar to that of tumor suppressor genes. In addition, this analysis showed that RBM10 mutations identified in LUAD patients lacking canonical oncogenes are associated with significantly reduced RBM10 expression...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28089820/deregulated-expression-of-vhl-mrna-variants-in-papillary-thyroid-cancer
#2
Enke Baldini, Chiara Tuccilli, Yannick Arlot-Bonnemains, Frank Chesnel, Salvatore Sorrenti, Corrado De Vito, Antonio Catania, Eleonora D'Armiento, Alessandro Antonelli, Poupak Fallahi, Sara Watutantrige-Fernando, Francesco Tartaglia, Susi Barollo, Caterina Mian, Marco Bononi, Stefano Arceri, Domenico Mascagni, Massimo Vergine, Daniele Pironi, Massimo Monti, Angelo Filippini, Salvatore Ulisse
Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI)...
January 12, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28087881/role-of-stim2-in-cell-function-and-physiopathology
#3
Alejandro Berna-Erro, Isaac Jardin, Gines M Salido, Juan A Rosado
An endoplasmic reticulum (ER)-resident protein that regulates cytosolic and ER free-Ca(2+) concentration by induction of store-operated calcium entry. That is the original definition of STIM2 and its function. While its activity strongly depends on the amount of calcium stored in the ER, its function goes further to intracellular signalling and gene expression. Initially undercovered by the prominent function of STIM1, STIM2 became to be vital in mice, gradually emerging as an important player in the nervous system, and cooperating with STIM1 in the immune system...
January 14, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28087715/sf3b1-hsh155-heat-motif-mutations-affect-interaction-with-the-spliceosomal-atpase-prp5-resulting-in-altered-branch-site-selectivity-in-pre-mrna-splicing
#4
Qing Tang, Susana Rodriguez-Santiago, Jing Wang, Jia Pu, Andrea Yuste, Varun Gupta, Alberto Moldón, Yong-Zhen Xu, Charles C Query
Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3' splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28086949/nek2-promotes-aerobic-glycolysis-in-multiple-myeloma-through-regulating-splicing-of-pyruvate-kinase
#5
Zhimin Gu, Jiliang Xia, Hongwei Xu, Ivana Frech, Guido Tricot, Fenghuang Zhan
BACKGROUND: Aerobic glycolysis, a hallmark of cancer, is characterized by increased metabolism of glucose and production of lactate in normaxia. Recently, pyruvate kinase M2 (PKM2) has been identified as a key player for regulating aerobic glycolysis and promoting tumor cell proliferation and survival. METHODS: Tandem affinity purification followed up by mass spectrometry (TAP-MS) and co-immunoprecipitation (Co-IP) were used to study the interaction between NIMA (never in mitosis gene A)-related kinase 2 (NEK2) and heterogeneous nuclear ribonucleoproteins (hnRNP) A1/2...
January 13, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28077788/androgen-receptor-splice-variants-and-prostate-cancer-from-bench-to-bedside
#6
REVIEW
Kristine M Wadosky, Shahriar Koochekpour
Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28069000/long-non-coding-rna-tug1-is-involved-in-cell-growth-and-chemoresistance-of-small-cell-lung-cancer-by-regulating-limk2b-via-ezh2
#7
Yuchun Niu, Feng Ma, Weimei Huang, Shun Fang, Man Li, Ting Wei, Linlang Guo
BACKGROUND: Taurine upregulated gene1 (TUG1) as a 7.1-kb lncRNA, has been shown to play an oncogenic role in various cancers. However, the biological functions of lncRNA TUG1 in small cell lung cancer (SCLC) remain unknown. The aim of this study is to explore the roles of TUG1 in cell growth and chemoresistance of SCLC and its possible molecular mechanism. METHODS: The expression of TUG1 in thirty-three cases of SCLC tissues and SCLC cell line were examined by quantitative RT-PCR (qRT-PCR)...
January 9, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28067246/mutant-u2af1-expressing-cells-are-sensitive-to-pharmacological-modulation-of-the-spliceosome
#8
Cara Lunn Shirai, Brian S White, Manorama Tripathi, Roberto Tapia, James N Ley, Matthew Ndonwi, Sanghyun Kim, Jin Shao, Alexa Carver, Borja Saez, Robert S Fulton, Catrina Fronick, Michelle O'Laughlin, Chandraiah Lagisetti, Thomas R Webb, Timothy A Graubert, Matthew J Walter
Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28062854/sf3b1-mutations-associated-with-myelodysplastic-syndromes-alter-the-fidelity-of-branchsite-selection-in-yeast
#9
Tucker J Carrocci, Douglas M Zoerner, Joshua C Paulson, Aaron A Hoskins
RNA and protein components of the spliceosome work together to identify the 5' splice site, the 3' splice site, and the branchsite (BS) of nascent pre-mRNA. SF3b1 plays a key role in recruiting the U2 snRNP to the BS. Mutations in human SF3b1 have been linked to many diseases such as myelodysplasia (MDS) and cancer. We have used SF3b1 mutations associated with MDS to interrogate the role of the yeast ortholog, Hsh155, in BS selection and splicing. These alleles change how the spliceosome recognizes the BS and alter splicing when nonconsensus nucleotides are present at the -2, -1 and +1 positions relative to the branchpoint adenosine...
January 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28062663/a-population-based-analysis-of-germline-bap1-mutations-in-melanoma
#10
Sally J O'Shea, Carla Daniela Robles-Espinoza, Lauren McLellan, Jeanine Harrigan, Xavier Jacq, James Hewinson, Vivek Iyer, Will Merchant, Faye Elliott, Mark Harland, D Timothy Bishop, Julia Newton-Bishop, David J Adams
Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found...
January 5, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28061334/arginine-methylation-the-coming-of-age
#11
REVIEW
Roméo S Blanc, Stéphane Richard
Arginine methylation is a common post-translational modification functioning as an epigenetic regulator of transcription and playing key roles in pre-mRNA splicing, DNA damage signaling, mRNA translation, cell signaling, and cell fate decision. Recently, a wealth of studies using transgenic mouse models and selective PRMT inhibitors helped define physiological roles for protein arginine methyltransferases (PRMTs) linking them to diseases such as cancer and metabolic, neurodegenerative, and muscular disorders...
January 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28060749/nido-amop-and-vwd-domains-of-muc4-play-synergic-role-in-muc4-mediated-signaling
#12
Yi Zhu, Jing-Jing Zhang, Yun-Peng Peng, Xian Liu, Kun-Ling Xie, Jie Tang, Kui-Rong Jiang, Wen-Tao Gao, Lei Tian, Kai Zhang, Ze-Kuan Xu, Yi Miao
MUC4 mucin is well known as an important potential target to overcome pancreatic cancer. Three unique domains (NIDO, AMOP, and vWD) with unclear roles only present in MUC4 but are not found in other membrane-bound mucins. Our previous studies first reported that its splice variant, MUC4/Y can be a model of MUC4 (MUC4 gene fragment is more than 30KB, too huge to clone and eukaryotic express) in pancreatic cancer. More importantly, based on MUC4/Y with the appropriate length of gene sequence, it is easy to construct the unique domain-lacking models of MUC4/Y (MUC4) for research...
January 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28060337/using-rna-sequencing-to-detect-novel-splice-variants-related-to-drug-resistance-in-in-vitro-cancer-models
#13
Rocco Sciarrillo, Anna Wojtuszkiewicz, Irsan E Kooi, Valentina E Gómez, Ugo Boggi, Gerrit Jansen, Gert-Jan Kaspers, Jacqueline Cloos, Elisa Giovannetti
Drug resistance remains a major problem in the treatment of cancer for both hematological malignancies and solid tumors. Intrinsic or acquired resistance can be caused by a range of mechanisms, including increased drug elimination, decreased drug uptake, drug inactivation and alterations of drug targets. Recent data showed that other than by well-known genetic (mutation, amplification) and epigenetic (DNA hypermethylation, histone post-translational modification) modifications, drug resistance mechanisms might also be regulated by splicing aberrations...
December 9, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28059167/splicing-imbalances-in-basal-like-breast-cancer-underpin-perturbation-of-cell-surface-and-oncogenic-pathways-and-are-associated-with-patients-survival
#14
Filipe Gracio, Brian Burford, Patrycja Gazinska, Anca Mera, Aisyah Mohd Noor, Pierfrancesco Marra, Cheryl Gillett, Anita Grigoriadis, Sarah Pinder, Andrew Tutt, Emanuele de Rinaldis
Despite advancements in the use of transcriptional information to understand and classify breast cancers, the contribution of splicing to the establishment and progression of these tumours has only recently starting to emerge. Our work explores this lesser known landscape, with special focus on the basal-like breast cancer subtype where limited therapeutic opportunities and no prognostic biomarkers are currently available. Using ExonArray analysis of 176 breast cancers and 9 normal breast tissues we demonstrate that splicing levels significantly contribute to the diversity of breast cancer molecular subtypes and explain much of the differences compared with normal tissues...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28059163/phosphoproteomic-comparison-of-pik3ca-and-pten-signalling-identifies-the-nucleotidase-nt5c-as-a-novel-akt-substrate
#15
Larissa S Moniz, Silvia Surinova, Essam Ghazaly, Lorena Gonzalez Velasco, Syed Haider, Juan Carlos Rodríguez-Prados, Inma M Berenjeno, Claude Chelala, Bart Vanhaesebroeck
To identify novel effectors and processes regulated by PI3K pathway activation, we performed an unbiased phosphoproteomic screen comparing two common events of PI3K deregulation in cancer: oncogenic Pik3ca mutation (Pik3ca(H1047R)) and deletion of Pten. Using mouse embryonic fibroblast (MEF) models that generate inducible, low-level pathway activation as observed in cancer, we quantified 7566 unique phosphopeptides from 3279 proteins. A number of proteins were found to be differentially-regulated by Pik3ca(H1047R) and Pten loss, suggesting unique roles for these two events in processes such as vesicular trafficking, DNA damage repair and RNA splicing...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28052032/a-novel-splice-variant-of-the-protein-tyrosine-phosphatase-ptprj-that-encodes-for-a-soluble-protein-involved-in-angiogenesis
#16
Anna Bilotta, Vincenzo Dattilo, Sabrina D'Agostino, Stefania Belviso, Stefania Scalise, Mariaconcetta Bilotta, Eugenio Gaudio, Francesco Paduano, Nicola Perrotti, Tullio Florio, Alfredo Fusco, Rodolfo Iuliano, Francesco Trapasso
PTPRJ is a receptor protein tyrosine phosphatase with tumor suppressor activity. Very little is known about the role of PTPRJ ectodomain, although recently both physiological and synthetic PTPRJ ligands have been identified. A putative shorter spliced variant, coding for a 539 aa protein corresponding to the extracellular N-terminus of PTPRJ, is reported in several databases but, currently, no further information is available.Here, we confirmed that the PTPRJ short isoform (named sPTPRJ) is a soluble protein secreted into the supernatant of both endothelial and tumor cells...
December 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/28052020/the-rna-binding-protein-esrp1-promotes-human-colorectal-cancer-progression
#17
Sharmila Fagoonee, Gabriele Picco, Francesca Orso, Arrigo Arrigoni, Dario L Longo, Marco Forni, Irene Scarfò, Adele Cassenti, Roberto Piva, Paola Cassoni, Lorenzo Silengo, Emanuela Tolosano, Silvio Aime, Daniela Taverna, Pier Paolo Pandolfi, Mara Brancaccio, Enzo Medico, Fiorella Altruda
Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific RNA binding protein that controls several key cellular processes, like alternative splicing and translation. Previous studies have demonstrated a tumor suppressor role for this protein. Recently, however, a pro-metastatic function of ESRP1 has been reported. We thus aimed at clarifying the role of ESRP1 in Colorectal Cancer (CRC) by performing loss- and gain-of-function studies, and evaluating tumorigenesis and malignancy with in vitro and in vivo approaches...
December 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/28050010/benchmarking-of-whole-exome-sequencing-and-ad-hoc-designed-panels-for-genetic-testing-of-hereditary-cancer
#18
Lídia Feliubadaló, Raúl Tonda, Mireia Gausachs, Jean-Rémi Trotta, Elisabeth Castellanos, Adriana López-Doriga, Àlex Teulé, Eva Tornero, Jesús Del Valle, Bernat Gel, Marta Gut, Marta Pineda, Sara González, Mireia Menéndez, Matilde Navarro, Gabriel Capellá, Ivo Gut, Eduard Serra, Joan Brunet, Sergi Beltran, Conxi Lázaro
Next generation sequencing panels have been developed for hereditary cancer, although there is some debate about their cost-effectiveness compared to exome sequencing. The performance of two panels is compared to exome sequencing. Twenty-four patients were selected: ten with identified mutations (control set) and fourteen suspicious of hereditary cancer but with no mutation (discovery set). TruSight Cancer (94 genes) and a custom panel (122 genes) were assessed alongside exome sequencing. Eighty-three genes were targeted by the two panels and exome sequencing...
January 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28049773/crosstalk-between-alternatively-spliced-ugt1a-isoforms-and-colon-cancer-cell-metabolism
#19
Yannick Audet-Delage, Michele Rouleau, Melanie Rouleau, Joannie Roberge, Stephanie Miard, Frederic Picard, Bernard Tetu, Chantal Guillemette
Alternative splicing at the human glucuronosyltransferase 1 gene locus (UGT1) produces alternate isoforms UGT1A_i2s that control glucuronidation activity through protein-protein interactions. Here, we hypothesized that UGT1A_i2s function into a complex protein network connecting other metabolic pathways with influence on cancer cell metabolism. This is based on a pathway enrichment analysis of proteomic data that identified several high-confidence candidate interaction proteins of UGT1A_i2 proteins in human tissues, namely the rate-limiting enzyme of glycolysis pyruvate kinase (PKM), which plays a critical role in cancer cell metabolism and tumor growth...
January 3, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28049589/a-triple-exon-skipping-luciferase-reporter-assay-identifies-a-new-clk-inhibitor-pharmacophore
#20
Yihui Shi, Jaehyeon Park, Chandraiah Lagisetti, Wei Zhou, Lidia C Sambucetti, Thomas R Webb
The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors...
December 24, 2016: Bioorganic & Medicinal Chemistry Letters
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