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Splicing inhibitor

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https://www.readbyqxmd.com/read/28433559/the-kcnh2-ivs9-28a-g-mutation-causes-aberrant-isoform-expression-and-herg-trafficking-defect-in-cardiomyocytes-derived-from-patients-affected-by-long-qt-syndrome-type-2
#1
Manuela Mura, Ashish Mehta, Chrishan J Ramachandra, Rita Zappatore, Federica Pisano, Maria Chiara Ciuffreda, Vincenzo Barbaccia, Lia Crotti, Peter J Schwartz, Winston Shim, Massimiliano Gnecchi
BACKGROUND: Long QT Syndrome type 2 (LQT2) is caused by mutations in the KCNH2 gene that encodes for the α-subunit (hERG) of the ion channel conducting the rapid delayed rectifier potassium current (IKr). We have previously identified a disease causing mutation (IVS9-28A/G) in the branch point of the splicing of KCNH2 intron 9. However, the mechanism through which this mutation causes the disease is unknown. METHODS AND RESULTS: We generated human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from fibroblasts of two IVS9-28A/G mutation carriers...
April 12, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28431339/novel-coumarin-and-quinolinone-based-polycycles-as-cell-division-cycle-25-a-and-c-phosphatases-inhibitors-induce-proliferation-arrest-and-apoptosis-in-cancer-cells
#2
Clemens Zwergel, Brigitte Czepukojc, Emilie Evain-Bana, Zhanjie Xu, Giulia Stazi, Mattia Mori, Alexandros Patsilinakos, Antonello Mai, Bruno Botta, Rino Ragno, Denise Bagrel, Gilbert Kirsch, Peter Meiser, Claus Jacob, Mathias Montenarh, Sergio Valente
Cell division cycle phosphatases CDC25 A, B and C are involved in modulating cell cycle processes and are found overexpressed in a large panel of cancer typology. Here, we describe the development of two novel quinone-polycycle series of CDC25A and C inhibitors on the one hand 1a-k, coumarin-based, and on the other 2a-g, quinolinone-based, which inhibit either enzymes up to a sub-micro molar level and at single-digit micro molar concentrations, respectively. When tested in six different cancer cell lines, compound 2c displayed the highest efficacy to arrest cell viability, showing in almost all cell lines sub-micro molar IC50 values, a profile even better than the reference compound NCS95397...
April 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28427194/alternative-rna-splicing-of-the-meaf6-gene-facilitates-neuroendocrine-prostate-cancer-progression
#3
Ahn R Lee, Yinan Li, Ning Xie, Martin E Gleave, Michael E Cox, Colin C Collins, Xuesen Dong
Although potent androgen receptor pathway inhibitors (ARPI) improve overall survival of metastatic prostate cancer patients, treatment-induced neuroendocrine prostate cancer (t-NEPC) as a consequence of the selection pressures of ARPI is becoming a more common clinical issue. Improved understanding of the molecular biology of t-NEPC is essential for the development of new effective management approaches for t-NEPC. In this study, we identify a splice variant of the MYST/Esa1-associated factor 6 (MEAF6) gene, MEAF6-1, that is highly expressed in both t-NEPC tumor biopsies and neuroendocrine cell lines of prostate and lung cancers...
March 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414204/docking-based-structural-splicing-and-reassembly-strategy-to-develop-novel-deazapurine-derivatives-as-potent-b-raf-v600e-inhibitors
#4
Gui-Min Wang, Xiang Wang, Jian-Ming Zhu, Bin-Bin Guo, Zhuo Yang, Zhi-Jian Xu, Bo Li, He-Yao Wang, Ling-Hua Meng, Wei-Liang Zhu, Jian Ding
The mutation of B-Raf(V600E) is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Raf(V600E) is an ideal drug target. This study focused on developing novel B-Raf(V600E) inhibitors as drug leads against various cancers with B-Raf(V600E) mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments...
April 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28404519/proteasome-inhibitors-to-alleviate-aberrant-ikbkap-mrna-splicing-and-low-ikap-help1-synthesis-in-familial-dysautonomia
#5
Mylène Hervé, El Chérif Ibrahim
FD is a rare neurodegenerative disorder caused by a mutation of the IKBKAP gene, which induces low expression levels of the Elongator subunit IKAP/hELP1 protein. A rational strategy for FD treatment could be to identify drugs increasing IKAP/hELP1 expression levels by blocking protein degradation pathways such as the 26S proteasome. Proteasome inhibitors are promising molecules emerging in cancer treatment and could thus constitute an enticing pharmaceutical strategy for FD treatment. Therefore, we tested three proteasome inhibitors on FD human olfactory ecto-mesenchymal stem cells (hOE-MSCs): two approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), bortezomib and carfilzomib, as well as epoxomicin...
April 9, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28397338/glycogen-synthase-kinase-3-inhibitors-suppress-the-ar-v7-mediated-transcription-and-selectively-inhibit-cell-growth-in-ar-v7-positive-prostate-cancer-cells
#6
Daisuke Nakata, Ryokichi Koyama, Kazuhide Nakayama, Satoshi Kitazawa, Tatsuya Watanabe, Takahito Hara
BACKGROUND: Recent evidence suggests that androgen receptor (AR) splice variants, including AR-V7, play a pivotal role in resistance to androgen blockade in prostate cancer treatment. The development of new therapeutic agents that can suppress the transcriptional activities of AR splice variants has been anticipated as the next generation treatment of castration-resistant prostate cancer. METHODS: High-throughput screening of AR-V7 signaling inhibitors was performed using an AR-V7 reporter system...
April 10, 2017: Prostate
https://www.readbyqxmd.com/read/28389374/a-novel-brca1-associated-protein-1-isoform-affects-response-of-mesothelioma-cells-to-drugs-impairing-brca1-mediated-dna-repair
#7
Rossella Parrotta, Agata Okonska, Manuel Ronner, Walter Weder, Rolf Stahel, Lorenza Penengo, Emanuela Felley-Bosco
INTRODUCTION: BRCA1-associated protein-1, BAP1, is a tumor suppressor involved in multiple cellular processes such as transcriptional regulation, chromatin modification by deubiquitinating histone 2A and DNA repair. BAP1 mutations are frequent in malignant pleural mesothelioma (MPM). Our aim was to functionally characterize a newly identified isoform of BAP1 and investigate the effects of its expression on drug sensitivity in MPM. METHODS: Expression of BAP1 isoforms was detected by qPCR in MPM and normal mesothelium cell lines, tumor and non-tumor samples...
April 4, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28389270/combination-of-valproic-acid-and-morpholino-splice-switching-oligonucleotide-produces-improved-outcomes-in-spinal-muscular-atrophy-patient-derived-fibroblasts
#8
Anna Farrelly-Rosch, Chew Ling Lau, Nitin Patil, Bradley J Turner, Fazel Shabanpoor
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality worldwide, is characterised by the homozygous loss of the survival motor neuron 1 (SMN1) gene. The consequent degeneration of spinal motor neurons and progressive atrophy of voluntary muscle groups results in paralysis and eventually premature infantile death. Humans possess a second nearly identical copy of SMN1, known as SMN2. However, SMN2 produces only 10-20% functional SMN protein due to aberrant splicing of its pre-mRNA that leads to the exclusion of exon 7...
April 4, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28377785/organellar-gene-expression-and-acclimation-of-plants-to-environmental-stress
#9
REVIEW
Dario Leister, Liangsheng Wang, Tatjana Kleine
Organelles produce ATP and a variety of vital metabolites, and are indispensable for plant development. While most of their original gene complements have been transferred to the nucleus in the course of evolution, they retain their own genomes and gene-expression machineries. Hence, organellar function requires tight coordination between organellar gene expression (OGE) and nuclear gene expression (NGE). OGE requires various nucleus-encoded proteins that regulate transcription, splicing, trimming, editing, and translation of organellar RNAs, which necessitates nucleus-to-organelle (anterograde) communication...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28377597/dyrk1a-overexpression-leads-to-increase-of-3r-tau-expression-and-cognitive-deficits-in-ts65dn-down-syndrome-mice
#10
Xiaomin Yin, Nana Jin, Jianhua Shi, Yanchong Zhang, Yue Wu, Cheng-Xin Gong, Khalid Iqbal, Fei Liu
Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau and 4R-tau, which is equally expressed in adult human brain. Imbalanced expression in 3R-tau and 4R-tau has been found in several sporadic and inherited tauopathies, suggesting that dysregulation of tau exon 10 is sufficient to cause neurodegenerative diseases. We previously reported that Dyrk1A, which is overexpressed in Down syndrome brains, regulates alternative splicing of exogenous tau exon 10...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28369518/misregulation-of-calcium-handling-proteins-promotes-hyperactivation-of-calcineurin-nfat-signaling-in-skeletal-muscle-of-dm1-mice
#11
Aymeric Ravel-Chapuis, Guy Bélanger, Jocelyn Côté, Robin N Michel, Bernard J Jasmin
Myotonic Dystrophy type 1 (DM1) is caused by an expansion of CUG repeats in DMPK mRNAs. This mutation affects alternative splicing through misregulation of RNA-binding proteins. Amongst pre-mRNAs that are misspliced, several code for proteins involved in calcium homeostasis suggesting that calcium-handling and signaling are perturbed in DM1. Here, we analyzed expression of such proteins in DM1 mouse muscle. We found that the levels of several sarcoplasmic reticulum proteins (SERCA1, sarcolipin and calsequestrin) are altered, likely contributing to an imbalance in calcium homeostasis...
March 27, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28358962/vegf-as-a-paracrine-regulator-of-conventional-outflow-facility
#12
Ester Reina-Torres, Joanne C Wen, Katy C Liu, Guorong Li, Joseph M Sherwood, Jason Y H Chang, Pratap Challa, Cassandra M Flügel-Koch, W Daniel Stamer, R Rand Allingham, Darryl R Overby
Purpose: Vascular endothelial growth factor (VEGF) regulates microvascular endothelial permeability, and the permeability of Schlemm's canal (SC) endothelium influences conventional aqueous humor outflow. We hypothesize that VEGF signaling regulates outflow facility. Methods: We measured outflow facility (C) in enucleated mouse eyes perfused with VEGF-A164a, VEGF-A165b, VEGF-D, or inhibitors to VEGF receptor 2 (VEGFR-2). We monitored VEGF-A secretion from human trabecular meshwork (TM) cells by ELISA after 24 hours of static culture or cyclic stretch...
March 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28347276/herboxidiene-triggers-splicing-repression-and-abiotic-stress-responses-in-plants
#13
Sahar AlShareef, Yu Ling, Haroon Butt, Kiruthiga G Mariappan, Moussa Benhamed, Magdy M Mahfouz
BACKGROUND: Constitutive and alternative splicing of pre-mRNAs from multiexonic genes controls the diversity of the proteome; these precisely regulated processes also fine-tune responses to cues related to growth, development, and stresses. Small-molecule inhibitors that perturb splicing provide invaluable tools for use as chemical probes to uncover the molecular underpinnings of splicing regulation and as potential anticancer compounds. RESULTS: Here, we show that herboxidiene (GEX1A) inhibits both constitutive and alternative splicing...
March 27, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28315432/splicing-factors-of-sr-and-hnrnp-families-as-regulators-of-apoptosis-in-cancer
#14
Hanna Kędzierska, Agnieszka Piekiełko-Witkowska
SR and hnRNP proteins were initially discovered as regulators of alternative splicing: the process of controlled removal of introns and selective joining of exons through which multiple transcripts and, subsequently, proteins can be expressed from a single gene. Alternative splicing affects genes involved in all crucial cellular processes, including apoptosis. During cancerogenesis impaired apoptotic control facilitates survival of cells bearing molecular aberrations, contributing to their unrestricted proliferation and chemoresistance...
March 14, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28302904/pharmacological-inhibition-of-the-spliceosome-subunit-sf3b-triggers-ejc-independent-nmd
#15
Teresa Carvalho, Sandra Martins, José Rino, Sérgio Marinho, Maria Carmo-Fonseca
Spliceostatin A, meayamycin, and pladienolide B are small molecules that target the SF3b subunit of spliceosomal U2 snRNP. These compounds are attracting much attention as tools to manipulate splicing and potential anti-cancer drugs. We investigated the effects of these inhibitors on mRNA transport and stability in human cells. Upon splicing inhibition unspliced pre-mRNAs accumulated in the nucleus, particularly within enlarged nuclear speckles. Yet, a small fraction of the pre-mRNA molecules were exported to the cytoplasm...
March 16, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28302793/anticancer-sulfonamides-target-splicing-by-inducing-rbm39-degradation-via-recruitment-to-dcaf15
#16
Ting Han, Maria Goralski, Nicholas Gaskill, Emanuela Capota, Jiwoong Kim, Tabitha C Ting, Yang Xie, Noelle S Williams, Deepak Nijhawan
Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity are unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with pre-mRNA splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing...
March 16, 2017: Science
https://www.readbyqxmd.com/read/28301600/the-hdac-inhibitor-sb939-overcomes-resistance-to-bcr-abl-kinase-inhibitors-conferred-by-the-bim-deletion-polymorphism-in-chronic-myeloid-leukemia
#17
Muhammad Rauzan, Charles T H Chuah, Tun Kiat Ko, S Tiong Ong
Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance...
2017: PloS One
https://www.readbyqxmd.com/read/28300534/identification-of-a-small-molecule-inhibitor-that-stalls-splicing-at-an-early-step-of-spliceosome-activation
#18
Anzhalika Sidarovich, Cindy L Will, Maria M Anokhina, Javier Ceballos, Sonja Sievers, Dmitry E Agafonov, Timur Samatov, Penghui Bao, Berthold Kastner, Henning Urlaub, Herbert Waldmann, Reinhard Lührmann
Small molecule inhibitors of pre-mRNA splicing are important tools for identifying new spliceosome assembly intermediates, allowing a finer dissection of spliceosome dynamics and function. Here, we identified a small molecule that inhibits human pre-mRNA splicing at an intermediate stage during conversion of pre-catalytic spliceosomal B complexes into activated B(act) complexes. Characterization of the stalled complexes (designated B(028)) revealed that U4/U6 snRNP proteins are released during activation before the U6 Lsm and B-specific proteins, and before recruitment and/or stable incorporation of Prp19/CDC5L complex and other B(act) complex proteins...
March 16, 2017: ELife
https://www.readbyqxmd.com/read/28296343/a-genome-wide-sirna-screen-for-regulators-of-tumor-suppressor-p53-activity-in-human-non-small-lung-cancer-cells-identifies-components-of-the-rna-splicing-machinery-as-targets-for-anticancer-treatment
#19
Ellen Siebring-van Olst, Maxime Blijlevens, Renee X de Menezes, Ida H van der Meulen-Muileman, Egbert F Smit, Victor W van Beusechem
Reinstating wild-type tumor suppressor p53 activity could be a valuable option for the treatment of cancer. To contribute to development of new treatment options for non-small cell lung cancer (NSCLC), we performed genome-wide siRNA screens for determinants of p53 activity in NSCLC cells. We identified many genes not previously known to be involved in regulating p53 activity. Silencing p53 pathway inhibitor genes was associated with loss of cell viability. The largest functional gene cluster influencing p53 activity was mRNA splicing...
March 13, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28289330/the-heterogeneity-of-cancer-stem-like-cells-at-the-invasive-front
#20
Go J Yoshida
Cancer stem-like cells exhibit the multi-functional roles to survive and persist for a long period in the minimal residual disease after the conventional anti-cancer treatments. Cancer stem-like cells of solid malignant tumors which highly express CD44v8-10, the variant isoform of CD44 generated by alternative splicing, has a resistance to redox stress by the robust production of glutathione mediated by ESRP1-CD44v-xCT (cystine/glutamate antiporter) axis. It has been reported that CD44v and c-Myc tend to show the inversed expression pattern at the invasive front of the aggressive tumors...
2017: Cancer Cell International
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