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Splicing inhibitor

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https://www.readbyqxmd.com/read/28315432/splicing-factors-of-sr-and-hnrnp-families-as-regulators-of-apoptosis-in-cancer
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/28283335/discovery-of-selective-atp-competitive-eif4a3-inhibitors
#8
Masahiro Ito, Misa Iwatani, Yusuke Kamada, Satoshi Sogabe, Shoichi Nakao, Toshio Tanaka, Tomohiro Kawamoto, Samuel Aparicio, Atsushi Nakanishi, Yasuhiro Imaeda
Eukaryotic initiation factor 4A3 (eIF4A3), an ATP-dependent RNA helicase, is a core component of exon junction complex (EJC). EJC has a variety of roles in RNA metabolism such as translation, surveillance, and localization of spliced RNA. It is worthwhile to identify selective eIF4A3 inhibitors with a view to investigating the functions of eIF4A3 and EJC further to clarify the roles of the ATPase and helicase activities in cells. Our chemical optimization of hit compound 2 culminated in the discovery of ATP-competitive eIF4A3 inhibitor 18 with submicromolar ATPase inhibitory activity and excellent selectivity over other helicases...
February 20, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28281569/treating-triple-negative-breast-cancer-cells-with-erlotinib-plus-a-select-antioxidant-overcomes-drug-resistance-by-targeting-cancer-cell-heterogeneity
#9
Bin Bao, Cristina Mitrea, Priyanga Wijesinghe, Luca Marchetti, Emily Girsch, Rebecca L Farr, Julie L Boerner, Ramzi Mohammad, Greg Dyson, Stanley R Terlecky, Aliccia Bollig-Fischer
Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes...
March 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28277851/management-of-lower-risk-myelodysplastic-syndromes-without-del5q-current-approach-and-future-trends
#10
Maximilian Stahl, Amer M Zeidan
Myelodysplastic syndromes (MDS) are characterized by progressive bone marrow failure manifesting as blood cytopenia and a variable risk of progression into acute myeloid leukemia. MDS is heterogeneous in biology and clinical behavior. MDS is generally divided into lower-risk (LR) or higher-risk (HR) MDS. Goals of care in HR-MDS is changing the natural history of the disease, whereas in LR-MDS it is symptom control and quality of life. Areas covered: We review the epidemiology, tools of risk assessment, and the available therapeutic modalities for LR-MDS...
February 21, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28266558/selective-induction-of-alternatively-spliced-fynt-isoform-by-tnf-facilitates-persistent-inflammatory-responses-in-astrocytes
#11
Chingli Lee, Clara Y B Low, Siew Ying Wong, Mitchell K P Lai, Michelle G K Tan
Fyn tyrosine kinase has been implicated in the pathogenesis of Alzheimer's disease (AD). We have previously reported that upregulation of the FynT isoform in AD brains was partly associated with astrocyte activation. In this study, we demonstrated selective FynT induction in murine cortex and primary astrocyte culture after prolonged exposure to inflammatory stimulants, suggesting that FynT may mediate persistent neuroinflammation. To delineate the functional role of astrocytic FynT in association with TNF-mediated inflammatory responses, immortalized normal human astrocytes (iNHA) stably expressing FynT kinase constitutively active (FynT-CA) or kinase dead (FynT-KD) mutants were treated with TNF and compared for inflammatory responses using high-throughput real-time RT-PCR and Luminex multi-analyte immunoassays...
March 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28263964/total-rna-seq-to-identify-pharmacological-effects-on-specific-stages-of-mrna-synthesis
#12
Sarah A Boswell, Andrew Snavely, Heather M Landry, L Stirling Churchman, Jesse M Gray, Michael Springer
Pharmacological perturbation is a powerful tool for understanding mRNA synthesis, but identification of the specific steps of this multi-step process that are targeted by small molecules remains challenging. Here we applied strand-specific total RNA sequencing (RNA-seq) to identify and distinguish specific pharmacological effects on transcription and pre-mRNA processing in human cells. We found unexpectedly that the natural product isoginkgetin, previously described as a splicing inhibitor, inhibits transcription elongation...
March 6, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28263841/the-formation-and-modification-of-chromatin-like-structure-of-human-parvovirus-b19-regulate-viral-genome-replication-and-rna-processing
#13
Huanzhou Xu, Sujuan Hao, Junmei Zhang, Zhen Chen, Hanzhong Wang, Wuxiang Guan
B19 virus (B19V) is a single stranded virus in the genus of Erythroparvovirus in the family of Parvoviridae. One of the limiting steps of B19V infection is the replication of viral genome which affected the alternative processing of its RNA. Minute virus of mice (MVM) and adeno-associated virus (AAV) has been reported to form chromatin-like structure within hours after infection of cells. However, the role of chromatin-like structure is unclear. In the present study, we found that B19V formed chromatin-like structure after 12h when B19V infectious clone was co-transfected with pHelper plasmid to HEK293T cells...
March 2, 2017: Virus Research
https://www.readbyqxmd.com/read/28259733/nfkbiz-in-psoriasis-assessing-the-association-with-gene-polymorphisms-and-report-of-a-new-transcript-variant
#14
Pablo Coto-Segura, Leire Gonzalez-Lara, Juan Gómez, Noemí Eiris, Ana Batalla, Celia Gómez, Sheila Requena, Rubén Queiro, Belén Alonso, Sara Iglesias, Eliecer Coto
The IκBζ protein (NFKBIZ gene) is a nuclear inhibitor of NF-κB and plays an important role in the pathogenesis of Psoriasis (Psor). We sought to determine whether common NFKBIZ variants were associated with the risk of developing Psor. A total of 392 patients and 336 controls were genotyped for a common intron 10 indel that could affect pre-mRNA splicing. We found a significantly higher frequency of the insertion among the cw6-positive patients (p=0.01). Cw6-positive+intron 10 ins/ins were significantly more frequent in the patients (OR=3...
March 1, 2017: Human Immunology
https://www.readbyqxmd.com/read/28257282/wt1-mutation-associated-nephropathy-a%C3%A2-single-center-experience%C3%A2
#15
Zhihui Yue, Haiyan Wang, Hongrong Lin, Juan Yang, Ting Liu, Yulin Liu, Huamu Chen, Liangzhong Sun
This study explored Wilms' tumor 1 (WT1) mutations in children with, or suspected of having, steroid-resistant nephrotic syndrome (SRNS), referred to or treated in our hospital in the past 6 years as well as the correlation between genotype and phenotype in WT1 mutation-associated nephropathy in Chinese patients. In total, 76 patients participated in the study. WT1 mutations were identified in 15 patients, 5 of whom harbored splice-site mutations in intron 9. Four of these 5 patients exhibited early onset of nephropathy and rapid deterioration of renal function...
March 3, 2017: Clinical Nephrology
https://www.readbyqxmd.com/read/28256005/regulatory-role-of-n-6-methyladenosine-m-6-a-methylation-in-rna-processing-and-human-diseases
#16
Wenqiang Wei, Xinying Ji, Xiangqian Guo, Shaoping Ji
N(6) -methyladenosine (m(6) A) modification is an abundant and conservative RNA modification in bacterial and eukaryotic cells. m(6) A modification mainly occurs in the 3' untranslated regions (UTRs) and near the stop codons of mRNA. Diverse strategies have been developed for identifying m(6) A sites in single nucleotide resolution. Dynamic regulation of m(6) A is found in metabolism, embryogenesis and developmental processes, indicating a possible epigenetic regulation role along RNA processing and exerting biological functions...
March 3, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28248290/systems-based-analysis-of-rig-i-dependent-signalling-identifies-khsrp-as-an-inhibitor-of-rig-i-receptor-activation
#17
Stephen Soonthornvacharin, Ariel Rodriguez-Frandsen, Yingyao Zhou, Felipe Galvez, Nicholas J Huffmaster, Shashank Tripathi, Vinod R M T Balasubramaniam, Atsushi Inoue, Elisa de Castro, Hong Moulton, David A Stein, María Teresa Sánchez-Aparicio, Paul D De Jesus, Quy Nguyen, Renate König, Nevan J Krogan, Adolfo García-Sastre, Sunnie M Yoh, Sumit K Chanda
Retinoic acid-inducible gene I (RIG-I) receptor recognizes 5'-triphosphorylated RNA and triggers a signalling cascade that results in the induction of type-I interferon (IFN)-dependent responses. Its precise regulation represents a pivotal balance between antiviral defences and autoimmunity. To elucidate the cellular cofactors that regulate RIG-I signalling, we performed two global RNA interference analyses to identify both positive and negative regulatory nodes operating on the signalling pathway during virus infection...
March 1, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28235766/sigma1-targeting-to-suppress-aberrant-androgen-receptor-signaling-in-prostate-cancer
#18
Jeffrey D Thomas, Charles G Longen, Halley M Oyer, Nan Chen, Christina M Maher, Joseph M Salvino, Blase Kania, Kelsey N Anderson, William F Ostrander, Karen E Knudsen, Felix J Kim
Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways...
February 24, 2017: Cancer Research
https://www.readbyqxmd.com/read/28228415/reduced-skeletal-muscle-fiber-size-following-caloric-restriction-is-associated-with-calpain-mediated-proteolysis-and-attenuation-of-igf-1-signaling
#19
Yue Lu, Jennifer S Bradley, Sarah R McCoski, John M Gonzalez, Alan D Ealy, Sally E Johnson
Caloric restriction decreases skeletal muscle mass in mammals, principally due to a reduction in fiber size. The effect of suboptimal nutrient intake on skeletal muscle metabolic properties in neonatal calves was examined. The longissimus muscle (LM) was collected after 8 wks consuming a control (CON) or caloric restricted (CR) diet and muscle fiber size, gene expression and metabolic signal transduction activity was measured. Results revealed that CR animals had smaller (P < 0.05) LM fiber cross-sectional area than CON, as expected...
February 22, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28224650/androgen-receptor-splice-variants-are-not-substrates-of-nonsense-mediated-decay
#20
Atinuke S Ajiboye, David Esopi, Srinivasan Yegnasubramanian, Samuel R Denmeade
BACKGROUND: Androgen receptor (AR) splice variants have been clinically associated with progressive cancer, castration-resistance, and resistance to AR antagonists and androgen synthesis inhibitors. AR variants can be generated by genomic alterations and alternative splicing, and their expression is androgen-regulated. There has been a suggestion that AR variants bearing premature termination codons and coding for truncated proteins should be regulated by the nonsense-mediated decay (NMD) mRNA surveillance pathway, suggesting that either the NMD pathway is dysfunctional in variant-expressing cell lines or that variants are somehow able to evade degradation by NMD...
February 22, 2017: Prostate
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