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Splicing inhibitor

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https://www.readbyqxmd.com/read/28934469/hnrnp-l-controls-hpv16-rna-polyadenylation-and-splicing-in-an-akt-kinase-dependent-manner
#1
Naoko Kajitani, Jacob Glahder, Chengjun Wu, Haoran Yu, Kersti Nilsson, Stefan Schwartz
Inhibition of the Akt kinase activates HPV16 late gene expression by reducing HPV16 early polyadenylation and by activating HPV16 late L1 mRNA splicing. We identified 'hot spots' for RNA binding proteins at the early polyA signal and at splice sites on HPV16 late mRNAs. We observed that hnRNP L was associated with sequences at all HPV16 late splice sites and at the early polyA signal. Akt kinase inhibition resulted in hnRNP L dephosphorylation and reduced association of hnRNP L with HPV16 mRNAs. This was accompanied by an increased binding of U2AF65 and Sam68 to HPV16 mRNAs...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28931466/1-alpha-25-dihydroxyvitamin-d3-up-regulates-the-expression-of-2-types-of-human-intestinal-alkaline-phosphatase-alternative-splicing-variants-in-caco-2-cells-and-may-be-an-important-regulator-of-their-expression-in-gut-homeostasis
#2
Seiko Noda, Asako Yamada, Kanae Nakaoka, Masae Goseki-Sone
Vitamin D insufficiency is associated with a greater risk of osteoporosis and also influences skeletal muscle functions, differentiation, and development. The principal function of vitamin D in calcium homeostasis is to increase the absorption of calcium from the intestine, and the level of alkaline phosphatase (ALP) activity, a differentiation marker for intestinal epithelial cells, is regulated by vitamin D. Intestinal-type ALP is expressed at a high concentration in the brush border membrane of intestinal epithelial cells, and is known to be affected by several kinds of nutrients...
August 4, 2017: Nutrition Research
https://www.readbyqxmd.com/read/28927803/in-cell-production-of-a-genetically-encoded-library-based-on-the-%C3%AE-defensin-rtd-1-using-a-bacterial-expression-system
#3
Tao Bi, Yilong Li, Alexander Shekhtman, Julio A Camarero
We report the high-yield heterologous expression of bioactive θ-defensin RTD-1 inside Escherichia coli cells by making use of intracellular protein trans-splicing in combination with a high efficient split-intein. RTD-1 is a small backbone-cyclized polypeptide with three disulfide bridges and a natural inhibitor of anthrax lethal factor protease. Recombinant RTD-1 was natively folded and able to inhibit anthrax lethal factor protease. In-cell expression of RTD-1 was very efficient and yielded ≈0.7mg of folded RTD-1 per gram of wet E...
September 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28926611/activation-of-the-unfolded-protein-response-in-sarcoma-cells-treated-with-rapamycin-or-temsirolimus
#4
Joseph W Briggs, Ling Ren, Kristi R Chakrabarti, Yien Che Tsai, Allan M Weissman, Ryan J Hansen, Daniel L Gustafson, Yousuf A Khan, Jonathan D Dinman, Chand Khanna
Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells...
2017: PloS One
https://www.readbyqxmd.com/read/28920960/long-noncoding-rna-egfr-as1-mediates-epidermal-growth-factor-receptor-addiction-and-modulates-treatment-response-in-squamous-cell-carcinoma
#5
Daniel S W Tan, Fui Teen Chong, Hui Sun Leong, Shen Yon Toh, Dawn P Lau, Xue Lin Kwang, Xiaoqian Zhang, Gopinath M Sundaram, Gek San Tan, Mei Mei Chang, Boon Tin Chua, Wan Teck Lim, Eng Huat Tan, Mei Kim Ang, Tony K H Lim, Prabha Sampath, Balram Chowbay, Anders J Skanderup, Ramanuj DasGupta, N Gopalakrishna Iyer
Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes...
September 18, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28912529/evasion-of-regulatory-phosphorylation-by-an-alternatively-spliced-isoform-of-musashi2
#6
Melanie C MacNicol, Chad E Cragle, F Kennedy McDaniel, Linda L Hardy, Yan Wang, Karthik Arumugam, Yasir Rahmatallah, Galina V Glazko, Ania Wilczynska, Gwen V Childs, Daohong Zhou, Angus M MacNicol
The Musashi family of RNA binding proteins act to promote stem cell self-renewal and oppose cell differentiation predominantly through translational repression of mRNAs encoding pro-differentiation factors and inhibitors of cell cycle progression. During tissue development and repair however, Musashi repressor function must be dynamically regulated to allow cell cycle exit and differentiation. The mechanism by which Musashi repressor function is attenuated has not been fully established. Our prior work indicated that the Musashi1 isoform undergoes site-specific regulatory phosphorylation...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28901514/multimodal-actions-of-the-phytochemical-sulforaphane-suppress-both-ar-and-ar-v7-in-22rv1-cells-advocating-a-potent-pharmaceutical-combination-against-castration-resistant-prostate-cancer
#7
Namrata Khurana, Hogyoung Kim, Partha K Chandra, Sudha Talwar, Pankaj Sharma, Asim B Abdel-Mageed, Suresh C Sikka, Debasis Mondal
Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1)...
August 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28884683/characterisation-of-the-biflavonoid-hinokiflavone-as-a-pre-mrna-splicing-modulator-that-inhibits-senp
#8
Andrea Pawellek, Ursula Ryder, Triin Tammsalu, Lewis J King, Helmi Kreinin, Tony Ly, Ronald T Hay, Richard Hartley, Angus I Lamond
We have identified the plant biflavonoid hinokiflavone as an inhibitor of splicing in vitro and modulator of alternative splicing in cells. Chemical synthesis confirms hinokiflavone is the active molecule. Hinokiflavone inhibits splicing in vitro by blocking spliceosome assembly, leading to accumulation of the A complex. Cells treated with hinokiflavone show altered subnuclear organization specifically of splicing factors required for A complex formation, which relocalize together with SUMO1 and SUMO2 into enlarged nuclear speckles...
September 8, 2017: ELife
https://www.readbyqxmd.com/read/28879433/cbp-mediated-smn-acetylation-modulates-cajal-body-biogenesis-and-the-cytoplasmic-targeting-of-smn
#9
Vanesa Lafarga, Olga Tapia, Sahil Sharma, Rocio Bengoechea, Georg Stoecklin, Miguel Lafarga, Maria T Berciano
The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN...
September 6, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28878333/ligand-activation-induces-different-conformational-changes-in-cxcr3-receptor-isoforms-as-evidenced-by-plasmon-waveguide-resonance-pwr
#10
K Boyé, C Billottet, N Pujol, I D Alves, A Bikfalvi
The chemokine receptor CXCR3 plays important roles in angiogenesis, inflammation and cancer. Activation studies and biological functions of CXCR3 are complex due to the presence of spliced isoforms. CXCR3-A is known as a pro-tumor receptor whereas CXCR3-B exhibits anti-tumor properties. Here, we focused on the conformational change of CXCR3-A and CXCR3-B after agonist or antagonist binding using Plasmon Waveguide Resonance (PWR). Agonist stimulation induced an anisotropic response with very distinct conformational changes for the two isoforms...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28878028/basal-a-triple-negative-breast-cancer-cells-selectively-rely-on-rna-splicing-for-survival
#11
Stefanie Chan, Praveen Sridhar, Rory Kirchner, Ying Jie Lock, Zach Herbert, Silvia Buonamici, Peter Smith, Judy Lieberman, Fabio Petrocca
Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of one TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis and apoptosis...
September 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28871472/cytochrome-p450-2d6-and-parkinson-s-disease-polymorphism-metabolic-role-risk-and-protection
#12
REVIEW
Mohd Sami Ur Rasheed, Abhishek Kumar Mishra, Mahendra Pratap Singh
Cytochrome P450 (CYP) 2D6 is one of the most highly active, oxidative and polymorphic enzymes known to metabolize Parkinsonian toxins and clinically established anti-Parkinson's disease (PD) drugs. Albeit CYP2D6 gene is not present in rodents, its orthologs perform almost the similar function with imprecise substrate and inhibitor specificity. CYP2D6 expression and catalytic activity are found to be regulated at every stage of the central dogma except replication as well as at the epigenetic level. CYP2D6 gene codes for a set of alternate splice variants that give rise to a range of enzymes possessing variable catalytic activity...
September 4, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28857308/a-novel-splicing-isoform-of-protein-arginine-methyltransferase-1-prmt1-that-lacks-the-dimerization-arm-and-correlates-with-cellular-malignancy
#13
Odysseas Patounas, Ioanna Papacharalampous, Carmen Eckerich, Georgios S Markopoulos, Evangelos Kolettas, Frank O Fackelmayer
Methylation of arginine residues is an important modulator of protein function that is involved in epigenetic gene regulation, DNA damage response and RNA maturation, as well as in cellular signaling. The enzymes that catalyze this post-translational modification are called protein arginine methyltransferases (PRMTs), of which PRMT1 is the predominant enzyme. Human PRMT1 has previously been shown to occur in seven splicing isoforms, which are differentially abundant in different tissues, and have distinct substrate specificity and intracellular localization...
August 31, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28855353/met-grb2-signaling-associated-complexes-correlate-with-oncogenic-met-signaling-and-sensitivity-to-met-kinase-inhibitors
#14
Matthew A Smith, Thomas Licata, Aliya Lakhani, Marileila Varella-Garcia, Hans-Ulrich Schildhaus, Vincent Vuaroqueaux, Balazs Halmos, Alain Borczuk, Y Ann Chen, Ben C Creelan, Theresa A Boyle, Eric B Haura
PURPOSE: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments. EXPERIMENTAL DESIGN: We utilized biochemical approaches, cellular viability studies and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N=406) and patient-derived xenograft models of solid tumors (N=308)...
August 29, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28844715/manumycin-a-suppresses-exosome-biogenesis-and-secretion-via-targeted-inhibition-of-ras-raf-erk1-2-signaling-and-hnrnp-h1-in-castration-resistant-prostate-cancer-cells
#15
Amrita Datta, Hogyoung Kim, Madhu Lal, Lauren McGee, Adedoyin Johnson, Ahmed A Moustafa, Jennifer C Jones, Debasis Mondal, Marc Ferrer, Asim B Abdel-Mageed
Emerging evidence links exosomes to cancer progression by the trafficking of oncogenic factors and neoplastic reprogramming of stem cells. This necessitates identification and integration of functionally validated exosome-targeting therapeutics into current cancer management regimens. We employed quantitative high throughput screen on two libraries to identify exosome-targeting drugs; a commercially available collection of 1280 pharmacologically active compounds and a collection of 3300 clinically approved compounds...
August 24, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28843992/tracking-met-de-addiction-in-lung-cancer-a-road-towards-the-oncogenic-target
#16
REVIEW
S Pilotto, L Carbognin, N Karachaliou, P C Ma, R Rosell, G Tortora, E Bria
The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) asa group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype...
August 20, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28843399/valosin-containing-protein-p97-as-a-novel-therapeutic-target-in-acute-lymphoblastic-leukemia
#17
Gabriele Gugliotta, Makoto Sudo, Qi Cao, De-Chen Lin, Haibo Sun, Sumiko Takao, Ronan Le Moigne, Mark Rolfe, Sigal Gery, Markus Müschen, Michele Cavo, H Phillip Koeffler
B acute lymphoblastic leukemia (B-ALL) cells are distinctively vulnerable to endoplasmic reticulum (ER) stress. Recently, inhibition of p97 was shown to induce ER stress and subsequently cell death in solid tumors and in multiple myeloma. We investigated the role of a novel, orally available, p97 inhibitor (CB-5083; Cleave Biosciences) in B-ALL. CB-5083 induced a significant reduction in viability in 10 human B-ALL cell lines, harboring the most common fusion-genes involved in pediatric and adult B-ALL, with IC50s ranging from 0...
August 24, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28842502/bngr-a25l-and-a27-are-two-functional-g-protein-coupled-receptors-for-capa-periviscerokinin-neuropeptides-in-the-silkworm-bombyx-mori
#18
Zhangfei Shen, Yu Chen, Lingjuan Hong, Zhenteng Cui, Huipeng Yang, Xiaobai He, Ying Shi, Liangen Shi, Feng Han, Naiming Zhou
CAPA peptides such as periviscerokinin (PVK) are insect neuropeptides involved in many signaling pathways controlling, for example, metabolism, behavior, and reproduction. They are present in a large number of insects and together with their cognate receptors, are important for research into approaches for improving insect control. However, the CAPA receptors in the silkworm (Bombyx mori) insect model are unknown. Here, we cloned cDNAs of two putative CAPA peptide receptor genes, BNGR-A27 and -A25, from the brain of B...
August 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28832644/3-o-trans-p-coumaroyl-alphitolic-acid-a-triterpenoid-from-zizyphus-jujuba-leads-to-apoptotic-cell-death-in-human-leukemia-cells-through-reactive-oxygen-species-production-and-activation-of-the-unfolded-protein-response
#19
Yohei Mitsuhashi, Yukihiro Furusawa, Tadashi Aradate, Qing-Li Zhao, Rohan Moniruzzaman, Masahiko Kanamori, Kyo Noguchi, Takashi Kondo
3-O-trans-p-coumaroyl-alphitolic acid (3OTPCA), a triterpenoid isolated from the plant Zizyphus jujuba (ZJ), is known to be cytotoxic to cancer cells; however, the molecular mechanism underlying 3OTPCA-induced cell death remains unknown. Here, we provide novel evidence that 3OTPCA induces apoptotic cell death in human leukemia cells. We found that 3OPTCA induces DNA fragmentation within 24 h after treatment in U937 cells, which was also observed in other leukemia cell lines, including Molt-4 and Jurkat cells...
2017: PloS One
https://www.readbyqxmd.com/read/28802831/validation-of-a-targeted-rna-sequencing-assay-for-kinase-fusion-detection-in-solid-tumors
#20
Julie W Reeser, Dorrelyn Martin, Jharna Miya, Esko A Kautto, Ezra Lyon, Eliot Zhu, Michele R Wing, Amy Smith, Matthew Reeder, Eric Samorodnitsky, Hannah Parks, Karan R Naik, Joseph Gozgit, Nicholas Nowacki, Kurtis D Davies, Marileila Varella-Garcia, Lianbo Yu, Aharon G Freud, Joshua Coleman, Dara L Aisner, Sameek Roychowdhury
Kinase gene fusions are important drivers of oncogenic transformation and can be inhibited with targeted therapies. Clinical grade diagnostics using RNA sequencing to detect gene rearrangements in solid tumors are limited, and the few that are available require prior knowledge of fusion break points. To address this, we have analytically validated a targeted RNA sequencing assay (OSU-SpARKFuse) for fusion detection that interrogates complete transcripts from 93 kinase and transcription factor genes. From a total of 74 positive and 36 negative control samples, OSU-SpARKFuse had 93...
August 8, 2017: Journal of Molecular Diagnostics: JMD
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