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Splicing inhibitor

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https://www.readbyqxmd.com/read/29164236/posttranscriptional-regulation-of-loxl1-expression-via-alternative-splicing-and-nonsense-mediated-mrna-decay-as-an-adaptive-stress-response
#1
Daniel Berner, Matthias Zenkel, Francesca Pasutto, Ursula Hoja, Panah Liravi, Gabriele C Gusek-Schneider, Friedrich E Kruse, Johannes Schödel, Andre Reis, Ursula Schlötzer-Schrehardt
Purpose: Alternative mRNA splicing coupled to nonsense-mediated decay (NMD) is a common mRNA surveillance pathway also known to dynamically modulate gene expression in response to cellular stress. Here, we investigated the involvement of this pathway in the regulation of lysyl oxidase-like 1 (LOXL1) expression in response to pseudoexfoliation (PEX)-associated pathophysiologic factors. Methods: Transcript levels of LOXL1 isoforms were determined in ocular tissues obtained from donor eyes without and with PEX syndrome...
November 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29150940/tumor-suppressive-roles-of-%C3%AE-np63%C3%AE-mir-205-axis-in-epithelial-mesenchymal-transition-of-oral-squamous-cell-carcinoma-via-targeting-zeb1-and-zeb2
#2
Yuma Hashiguchi, Shintaro Kawano, Yuichi Goto, Kaori Yasuda, Naoki Kaneko, Taiki Sakamoto, Ryota Matsubara, Teppei Jinno, Yasuyuki Maruse, Hideaki Tanaka, Masahiko Morioka, Taichi Hattori, Shoichi Tanaka, Tamotsu Kiyoshima, Seiji Nakamura
We previously revealed that epithelial-to-mesenchymal transition (EMT) was mediated by ΔNp63β, a splicing variant of ΔNp63, in oral squamous cell carcinoma (OSCC). Recent studies have highlighted the involvement of microRNA (miRNA) in EMT of cancer cells, though the mechanism remains unclear. To identify miRNAs responsible for ΔNp63β-mediated EMT, miRNA microarray analyses were performed by ΔNp63β-overexpression in OSCC cells; SQUU-B, which lacks ΔNp63 expression and displays EMT phenotypes. miRNAs microarray analyses revealed miR-205 was the most up-regulated following ΔNp63β-overexpression...
November 18, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29147905/transcriptional-regulation-of-dj-1
#3
Kazuko Takahashi-Niki, Takeshi Niki, Sanae M M Iguchi-Ariga, Hiroyoshi Ariga
DJ-1 is an oncogene and also a causative gene for familial Parkinson's disease. DJ-1 has various functions, and the oxidative status of a cysteine residue at position 106 (C106) is crucial for determination of the activation level of DJ-1.DJ-1 binds to many proteins, including various transcription factors, and acts as a coactivator or corepressor for regulating their target genes without direct binding to DNA, thereby affecting various cell functions. DJ-1-regulating transcription factors and their modified proteins are the androgen receptor and its regulatory proteins, p53; polypyrimidine tract-binding protein-associated splicing factor (PSF); Keap1, an inhibitor for nuclear factor erythroid2-related factor 2 (Nrf2); sterol regulatory element-binding protein (SREBP); Ras-responsive element-binding protein (RREB1); signal transducer and activator of transcription 1 (STAT1); and Nurr1...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29147733/-inhibitors-of-the-androgen-receptor-n%C3%A2-terminal-domain-therapies-targeting-the-achilles-heel-of-various-androgen-receptor-molecules-in-advanced-prostate-cancer
#4
REVIEW
M C Hupe, A Offermann, F Perabo, C Chandhasin, S Perner, A S Merseburger, M V Cronauer
Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR...
November 16, 2017: Der Urologe. Ausg. A
https://www.readbyqxmd.com/read/29142472/prostaglandin-e1-protects-hepatocytes-against-endoplasmic-reticulum-stress-induced-apoptosis-via-protein-kinase-a-dependent-induction-of-glucose-regulated-protein-78-expression
#5
Fang-Wan Yang, Yu Fu, Ying Li, Yi-Huai He, Mao-Yuan Mu, Qi-Chuan Liu, Jun Long, Shi-De Lin
AIM: To investigate the protective effect of prostaglandin E1 (PGE1) against endoplasmic reticulum (ER) stress-induced hepatocyte apoptosis, and to explore its underlying mechanisms. METHODS: Thapsigargin (TG) was used to induce ER stress in the human hepatic cell line L02 and hepatocarcinoma-derived cell line HepG2. To evaluate the effects of PGE1 on TG-induced apoptosis, PGE1 was used an hour prior to TG treatment. Activation of unfolded protein response signaling pathways were detected by western blotting and quantitative real-time RT-PCR...
October 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29142127/epstein-barr-virus-protein-eb2-stimulates-translation-initiation-of-mrnas-through-direct-interactions-with-both-pabp-and-eif4g
#6
Fabrice Mure, Baptiste Panthu, Isabelle Zanella-Cléon, Frédéric Delolme, Evelyne Manet, Théophile Ohlmann, Henri Gruffat
Epstein-Barr virus (EBV) expresses several mRNAs produced from intronless genes that could potentially be unfavorably translated compared to cellular spliced mRNAs. To overcome this situation, the virus encodes an RNA-binding protein (RBP) called EB2, previously found to both facilitate the export of nuclear mRNAs and increase their translational yield. Here, we show that EB2 binds both nuclear and cytoplasmic cap-binding complexes (respectively, CBC and eIF4F) as well as the poly(A)-binding protein (PABP) to enhance translation initiation of a given mRNP...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29133617/response-and-resistance-to-paradox-breaking-braf-inhibitor-in-melanomas-in-vivo-and-ex-vivo
#7
Edward J Hartsough, Curtis H Kugel, Michael J Vido, Adam C Berger, Timothy J Purwin, Allison Goldberg, Michael A Davies, Matthew J Schiewer, Karen E Knudsen, Gideon Bollag, Andrew E Aplin
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox breaking RAF inhibitor (PLX8394) has been designed. Here we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29129695/tetrahydroxystilbene-glucoside-modulates-amyloid-precursor-protein-processing-via-activation-of-akt-gsk3%C3%AE-pathway-in-cells-and-in-app-ps1-transgenic-mice
#8
Xiaomin Yin, Chen Chen, Ting Xu, Lin Li, Lan Zhang
Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aβ) production. Here, we determined the effect of TSG on the AKT-GSK3β pathway. We found GSK3β increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3β signaling pathway suppressed APP-KPI inclusion...
November 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29121914/splice-variants-of-the-extracellular-region-of-ron-receptor-tyrosine-kinase-in-lung-cancer-cell-lines-identified-by-pcr-and-sequencing
#9
Soundararajan Krishnaswamy, Abdul Khader Mohammed, Gyanendra Tripathi, Majed S Alokail, Nasser M Al-Daghri
BACKGROUND: Altered expression of receptor tyrosine kinases (RTKs) is a major driver of growth and metastasis of cancers. Recepteur d'origine nantais (RON) receptor is a single-pass transmembrane RTK aberrantly expressed in a number of cancers. Efforts to block deregulated RON signaling in tumors using small molecule kinase inhibitors or antibodies are complicated by the presence of unknown number/types of isoforms of RON, which, despite having similar sequences, are localized differently and mediate varied functions...
November 9, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29121415/efficacy-and-safety-of-trametinib-in-japanese-patients-with-advanced-biliary-tract-cancers-refractory-to-gemcitabine
#10
Masafumi Ikeda, Tatsuya Ioka, Akira Fukutomi, Chigusa Morizane, Akiyoshi Kasuga, Hideaki Takahashi, Akiko Todaka, Takuji Okusaka, Caretha L Creasy, Shelby Gorman, Daniel J Felitsky, Mikiro Kobayashi, Fanghong Zhang, Junji Furuse
Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this Phase IIa open-label, single-arm study, we investigated efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy...
November 9, 2017: Cancer Science
https://www.readbyqxmd.com/read/29114472/molecular-diagnostics-of-lung-cancer-in-the-clinic
#11
REVIEW
Lynette Sholl
According to current practice guidelines, all patients with advanced non-small cell lung cancer (NSCLC) should undergo predictive biomarker testing. For squamous cell carcinoma patients, PD-L1 immunohistochemistry is indicated to select patients for immunotherapy in the first line. For lung adenocarcinoma, all patients with advanced disease should undergo testing for epidermal growth factor receptor (EGFR) mutations, ALK and ROS1 rearrangements, and PD-L1 expression to predict response to EGFR, ALK, or ROS1 targeted inhibitors or immunotherapy, respectively...
October 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/29114070/srsf6-regulated-alternative-splicing-that-promotes-tumour-progression-offers-a-therapy-target-for-colorectal-cancer
#12
Ledong Wan, Wenying Yu, Enhui Shen, Wenjie Sun, Yuan Liu, Jianlu Kong, Yihua Wu, Fengyan Han, Lei Zhang, Tianze Yu, Yuwei Zhou, Sunzhe Xie, Enping Xu, Honghe Zhang, Maode Lai
OBJECTIVE: To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6. DESIGN: We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay...
November 7, 2017: Gut
https://www.readbyqxmd.com/read/29111855/neuroprotective-effects-of-inhibitors-of-acid-sensing-ion-channels-asics-in-optic-nerve-crush-model-in-rodents
#13
Dorota L Stankowska, Brett H Mueller, Hidehiro Oku, Tsunehiko Ikeda, Adnan Dibas
PURPOSE: The purpose of the current study was to assess the potential involvement of acid-sensing ion channel 1 (ASIC1) in retinal ganglion cell (RGC) death and investigate the neuroprotective effects of inhibitors of ASICs in promoting RGC survival following optic nerve crush (ONC). RESULTS: ASIC1 protein was significantly increased in optic nerve extracts at day 7 following ONC in rats. Activated calpain-1 increased at 2 and 7 days following ONC as evidenced by increased degradation of α-fodrin, known substrate of calpain...
November 7, 2017: Current Eye Research
https://www.readbyqxmd.com/read/29110173/combination-treatment-with-docetaxel-and-histone-deacetylase-inhibitors-downregulates-androgen-receptor-signaling-in-castration-resistant-prostate-cancer
#14
Sang Eun Park, Ha-Gyeong Kim, Dong Eun Kim, Yoo Jung Jung, Yunlim Kim, Seong-Yun Jeong, Eun Kyung Choi, Jung Jin Hwang, Choung-Soo Kim
Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting...
November 7, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29100409/overcoming-imatinib-resistance-conferred-by-the-bim-deletion-polymorphism-in-chronic-myeloid-leukemia-with-splice-switching-antisense-oligonucleotides
#15
Jun Liu, Malini Bhadra, Joanna Rajeswary Sinnakannu, Wan Lin Yue, Cheryl Weiqi Tan, Frank Rigo, S Tiong Ong, Xavier Roca
Many tyrosine kinase-driven cancers, including chronic myeloid leukemia (CML), are characterized by high response rates to specific tyrosine kinase inhibitors (TKIs) like imatinib. In East Asians, primary imatinib resistance is caused by a deletion polymorphism in Intron 2 of the BIM gene, whose product is required for TKI-induced apoptosis. The deletion biases BIM splicing from exon 4 to exon 3, generating splice isoforms lacking the exon 4-encoded pro-apoptotic BH3 domain, which impairs the ability of TKIs to induce apoptosis...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29100343/establishment-and-characterization-of-patient-derived-xenograft-models-of-gastrointestinal-stromal-tumor-resistant-to-standard-tyrosine-kinase-inhibitors
#16
Young-Soon Na, Min-Hee Ryu, Changhoon Yoo, Ju-Kyung Lee, Jung Min Park, Chae-Won Lee, Sun Young Lee, Young-Kyoung Shin, Ja-Lok Ku, Sung-Min Ahn, Yoon-Koo Kang
Gastrointestinal stromal tumors (GISTs) with KIT or platelet-derived growth factor receptor alpha (PDGFRa) oncogenic driver gene mutations, respond to tyrosine kinase inhibitors (TKIs) including imatinib, sunitinib, and regorafenib. However, most patients develop TKI resistance; therefore, novel agents are required. We established three TKI-resistant GIST patient-derived xenograft (PDX) models for effective drug development. These were PDX models harboring primary and secondary KIT and additional mutations; KIT exon 11 (p...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29099132/development-of-an-alphalisa-high-throughput-technique-to-screen-for-small-molecule-inhibitors-targeting-protein-arginine-methyltransferases
#17
Lakshmi Prabhu, Lan Chen, Han Wei, Özlem Demir, Ahmad Safa, Lifan Zeng, Rommie E Amaro, Bert H O'Neil, Zhon-Yin Zhang, Tao Lu
The protein arginine methyltransferase (PRMT) family of enzymes comprises nine family members in mammals. They catalyze arginine methylation, either monomethylation or symmetric/asymmetric dimethylation of histone and non-histone proteins. PRMT methylation of its substrate proteins modulates cellular processes such as signal transduction, transcription, and mRNA splicing. Recent studies have linked overexpression of PRMT5, a member of the PRMT superfamily, to oncogenesis, making it a potential target for cancer therapy...
November 21, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/29098149/regulation-of-ire1%C3%AE-by-the-small-molecule-inhibitor-4%C3%AE-8c-in-hepatoma-cells
#18
Claire Stewart, Andrea Estrada, Paul Kim, Dong Wang, Yuren Wei, Chris Gentile, Michael Pagliassotti
The unfolded protein response (UPR) is activated in response to impairments of the folding environment in the endoplasmic reticulum (ER). The most conserved arm of the UPR, inositol-requiring ER-to-nucleus signaling protein (IRE1α), has been linked to the regulation of a diverse array of cellular processes including ER-associated degradation, inflammatory signaling, cell proliferation and membrane biogenesis. Recent studies have utilized the selective, small molecule inhibitor, 4μ8c, to examine the role of IRE1α endoribonuclease (RNase) activity in various cell types including multiple myeloma, mouse embryonic fibroblasts and pancreatic beta cells [1-5]...
April 2017: Endoplasmic Reticulum Stress in Diseases
https://www.readbyqxmd.com/read/29090014/the-emerging-roles-of-cdk12-in-tumorigenesis
#19
REVIEW
Hana Paculová, Jiří Kohoutek
Cyclin-dependent kinases (CDKs) are key regulators of both cell cycle progression and transcription. Since dysregulation of CDKs is a frequently occurring event driving tumorigenesis, CDKs have been tested extensively as targets for cancer therapy. Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase which participates in various cellular processes, including DNA damage response, development and cellular differentiation, as well as splicing and pre-mRNA processing. CDK12 mutations and amplification have been recently reported in different types of malignancies, including loss-of-function mutations in high-grade serous ovarian carcinomas, and that has led to assumption that CDK12 is a tumor suppressor...
2017: Cell Division
https://www.readbyqxmd.com/read/29075790/differential-contribution-of-tissue-factor-and-factor%C3%A2-xii-to-thrombin-generation-triggered-by-breast-and-pancreatic-cancer-cells
#20
Aurélie Rousseau, Annette K Larsen, Patrick Van Dreden, Michele Sabbah, Ismail Elalamy, Grigoris T Gerotziafas
Most cancer cells trigger thrombin generation (TG) to various extent. In the present study, we dissected the mechanisms responsible for the procoagulant activity of pancreatic adenocarcinoma cells (BXPC3), a highly thrombogenic cancer type, and breast cancer cells (MCF7), a less thombogenic tumor type. TG of normal plasma was assessed by the Thrombinoscope (CAT®) in the presence or absence of cancer cells. TG was also assessed in plasma depleted of clotting factors, in plasma spiked with tissue factor (TF) and/or procoagulant phospholipids, in plasma spiked with an anti-TF monoclonal antibody or with corn trypsin inhibitor (CTI)...
October 20, 2017: International Journal of Oncology
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