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https://www.readbyqxmd.com/read/28735070/suppression-of-the-atp-binding-cassette-transporter-abcc4-impairs-neuroblastoma-tumour-growth-and-sensitises-to-irinotecan-in%C3%A2-vivo
#1
Jayne Murray, Emanuele Valli, Denise M T Yu, Alan M Truong, Andrew J Gifford, Georgina L Eden, Laura D Gamble, Kimberley M Hanssen, Claudia L Flemming, Alvin Tan, Amanda Tivnan, Sophie Allan, Federica Saletta, Leanna Cheung, Michelle Ruhle, John D Schuetz, Michelle J Henderson, Jennifer A Byrne, Murray D Norris, Michelle Haber, Jamie I Fletcher
The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts...
July 20, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28729373/the-importance-of-managing-the-patient-and-not-the-gene-expanded-phenotype-of-gle1-associated-arthrogryposis
#2
Queenie K-G Tan, Allyn McConkie-Rosell, Jane Juusola, Kathryn E Gustafson, Carolyn E Pizoli, Anne F Buckley, Yong-Hui Jiang
GLE1 encodes a protein important for mRNA export and appears to play roles in translation initiation and termination as well. Pathogenic variants in GLE1 mutations have been associated with lethal contracture syndrome (LCCS1) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD); phenotypes reported in individuals include fetal akinesia and a severe form of motor neuron disease, typically presenting with prenatal symptoms and perinatal lethality. In this paper, we identified bi-allelic missense mutations in GLE1 by trio whole exome sequencing (WES) in an individual affected with congenital motor weakness and contractures as well as feeding and respiratory difficulties...
July 20, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28719294/molecular-markers-for-sensitive-detection-of-plasmodium-falciparum-asexual-stage-parasites-and-their-application-in-a-malaria-clinical-trial
#3
Fitsum G Tadesse, Kjerstin Lanke, Issa Nebie, Jodie A Schildkraut, Bronner P Gonçalves, Alfred B Tiono, Robert Sauerwein, Chris Drakeley, Teun Bousema, Sanna R Rijpma
Plasmodium falciparum parasite life stages respond differently to antimalarial drugs. Sensitive stage-specific molecular assays may help to examine parasite dynamics at microscopically detectable and submicroscopic parasite densities in epidemiological and clinical studies. In this study, we compared the performance of skeleton-binding protein 1 (SBP1), ring-infected erythrocyte surface antigen, Hyp8, ring-exported protein 1 (REX1), and PHISTb mRNA for detecting ring-stage trophozoite-specific transcripts using quantitative reverse transcriptase polymerase chain reaction...
July 2017: American Journal of Tropical Medicine and Hygiene
https://www.readbyqxmd.com/read/28708448/quick-or-quality-how-mrna-escapes-nuclear-quality-control-during-stress
#4
Gesa Zander, Heike Krebber
Understanding the mechanisms for mRNA production under normal conditions and in response to cytotoxic stresses has been subject of numerous studies for several decades. The shutdown of canonical mRNA transcription, export and translation is required to have enough free resources for the immediate production of heat shock proteins that act as chaperones to sustain cellular processes. In recent work we uncovered a simple mechanism, in which the export block of regular mRNAs and a fast export of heat shock mRNAs is achieved by deactivation of the nuclear mRNA quality control mediated by the guard-protein...
July 14, 2017: RNA Biology
https://www.readbyqxmd.com/read/28706239/increased-adipose-tissue-heme-levels-and-exportation-are-associated-with-altered-systemic-glucose-metabolism
#5
José María Moreno-Navarrete, Amaia Rodríguez, Francisco Ortega, Sara Becerril, Mònica Sabater-Masdeu, Jessica Latorre, Wifredo Ricart, Gema Frühbeck, José Manuel Fernández-Real
Iron status is known to be associated with the physiology of adipose tissue (AT). We aimed to investigate AT heme and expression of heme exporter (FLVCR1) in association with obesity and type 2 diabetes (T2D). Substantial amounts of FLVCR1 mRNA and protein levels were detected in AT, being significantly increased in subjects with T2D, and positively correlated with fasting glucose, fasting triglycerides and with circulating markers of iron stores (serum ferritin, blood hemoglobin and hematocrit). In both visceral (VAT) and subcutaneous AT (SAT), increased heme levels were found in subjects with T2D...
July 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28705828/crispr-induced-null-alleles-show-that-frost-protects-drosophila-melanogaster-reproduction-after-cold-exposure
#6
Claire E Newman, Jantina Toxopeus, Hiroko Udaka, Soohyun Ahn, David M Martynowicz, Steffen P Graether, Brent J Sinclair, Anthony Percival-Smith
The ability to survive and reproduce after cold exposure is important in all kingdoms of life. However, even in a sophisticated genetic model system like Drosophila melanogaster, few genes have been identified as functioning in cold tolerance. The accumulation of the Frost (Fst) gene transcript increases after cold exposure, making it a good candidate for a gene that has a role in cold tolerance. However, despite extensive RNAi knockdown analysis, no role in cold tolerance has been assigned to Fst CRISPR is an effective technique for completely knocking down genes, and less likely to produce off-target effects than GAL4-UAS RNAi systems...
July 13, 2017: Journal of Experimental Biology
https://www.readbyqxmd.com/read/28696814/ddx19-links-mrna-nuclear-export-with-progression-of-transcription-and-replication-and-suppresses-genomic-instability-upon-dna-damage-in-proliferating-cells
#7
Dana Hodroj, Kamar Serhal, Domenico Maiorano
The DEAD-box Helicase 19 (Ddx19) gene codes for an RNA helicase involved in both messenger RNA (mRNA) export from the nucleus into the cytoplasm and in mRNA translation. In unperturbed cells, Ddx19 localizes in the cytoplasm and at the cytoplasmic face of the nuclear pore. Here we review recent findings related to an additional Ddx19 function in the nucleus in resolving RNA:DNA hybrids (R-loops) generated during collision between transcription and replication, and upon DNA damage. Activation of a DNA damage response pathway dependent upon the ATR kinase, a major regulator of replication fork progression, stimulates translocation of the Ddx19 protein from the cytoplasm into the nucleus...
July 11, 2017: Nucleus
https://www.readbyqxmd.com/read/28695513/methodology-to-identify-poly-adp-ribose-polymerase-1-parp1-mrna-targets-by-par-clip
#8
Manana Mekishvili, Elena Matveeva, Yvonne Fondufe-Mittendorf
There is a long list of important RNA-binding proteins (RBP) involved in different steps of gene expression through posttranscriptional modifications: pre-mRNA splicing, mRNA stabilization, polyadenylation, mRNA export from nucleus to the cytoplasm, and translation. The critical role of RNA-protein interaction necessitates a continuous identification of proteins involved in this process. Here we describe the identification of Poly-ADP-Ribose Polymerase 1 (PARP1) as an RNA binding protein involved in RNA splicing...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28691782/a-novel-microduplication-of-arid1b-clinical-genetic-and-proteomic-findings
#9
Catarina M Seabra, Nicholas Szoko, Serkan Erdin, Ashok Ragavendran, Alexei Stortchevoi, Patrícia Maciel, Kathleen Lundberg, Daniela Schlatzer, Janice Smith, Michael E Talkowski, James F Gusella, Marvin R Natowicz
Genetic alterations of ARID1B have been recently recognized as one of the most common mendelian causes of intellectual disability and are associated with both syndromic and non-syndromic phenotypes. The ARID1B protein, a subunit of the chromatin remodeling complex SWI/SNF-A, is involved in the regulation of transcription and multiple downstream cellular processes. We report here the clinical, genetic, and proteomic phenotypes of an individual with a unique apparent de novo mutation of ARID1B due to an intragenic duplication...
July 10, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28686487/nanoscale-invaginations-of-the-nuclear-envelope-shedding-new-light-on-wormholes-with-elusive-function
#10
Ingmar Schoen, Lina Aires, Jonas Ries, Viola Vogel
Recent advances in fluorescence microscopy have opened up new possibilities to investigate chromosomal and nuclear 3D organization on the nanoscale. We here discuss their potential for elucidating topographical details of the nuclear. Single molecule localization microscopy (SMLM) in combination with immunostainings of lamina proteins readily reveals tube-like invaginations with a diameter of 100-500 nm. Although these invaginations have been established as a frequent and general feature of interphase nuclei across different cell types, their formation mechanism and function have remained largely elusive...
July 7, 2017: Nucleus
https://www.readbyqxmd.com/read/28676422/kinetics-of-transport-through-the-nuclear-pore-complex
#11
REVIEW
Ulrich Kubitscheck, Jan-Peter Siebrasse
Single molecule microscopy techniques allow to visualize the translocation of single transport receptors and cargo molecules or particles through nuclear pore complexes. These data indicate that cargo molecule import into the nucleus takes less than 10 milliseconds and nuclear export of messenger RNA (mRNA) particles takes 50 to 350 milliseconds, up to several seconds for extremely bulky particles. This review summarizes and discusses experimental results on transport of nuclear transport factor 2 (NTF2), importin β and mRNA particles...
July 1, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/28673892/how-introns-enhance-gene-expression
#12
Orit Shaul
In many eukaryotes, including mammals, plants, yeast, and insects, introns can increase gene expression without functioning as a binding site for transcription factors. This phenomenon was termed 'intron-mediated enhancement'. Introns can increase transcript levels by affecting the rate of transcription, nuclear export, and transcript stability. Moreover, introns can also increase the efficiency of mRNA translation. This review discusses the current knowledge about these processes. The role of splicing in IME and the significance of intron position relative to the sites of transcription and translation initiation are elaborated...
June 30, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28672025/interleukin-6-regulates-iron-related-proteins-through-c-jun-n-terminal-kinase-activation-in-bv2-microglial-cell-lines
#13
Shida Zhou, Xinxing Du, Junxia Xie, Jun Wang
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) and subsequent DA depletion in the striatum. Microglia activation and nigral iron accumulation play important roles in the pathogenesis of PD. Activated microglia show increased iron deposits. However, the relationship between microglia activation and iron accumulation remains unclear. In the present study, we aimed to determine how iron levels affect interleukin-6 (IL-6) synthesis, and the effect of IL-6 on cellular iron metabolism in BV2 microglial cells...
2017: PloS One
https://www.readbyqxmd.com/read/28645914/bile-salt-homeostasis-in-normal-and-bsep-gene-knock-out-rats-with-single-and-repeated-doses-of-troglitazone
#14
Yaofeng Cheng, Shenjue Chen, Chris Freeden, Weiqi Chen, Yueping Zhang, Pamela Abraham, David Nelson, William G Humphreys, Jinpin Gan, Yurong Lai
The interference of bile acid secretion through bile salt export pump (BSEP) inhibition was one of the mechanisms for troglitazone (TGZ) induced hepatotoxicity. Here we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep KO rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on Day-1 and Day-7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7...
June 23, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28636910/prp40-homolog-a-is-a-novel-centrin-target
#15
Adalberto Díaz Casas, Walter J Chazin, Belinda Pastrana-Ríos
Pre-mRNA processing protein 40 (Prp40) is a nuclear protein that has a role in pre-mRNA splicing. Prp40 possesses two leucine-rich nuclear export signals, but little is known about the function of Prp40 in the export process. Another protein that has a role in protein export is centrin, a member of the EF-hand superfamily of Ca(2+)-binding proteins. Prp40 was found to be a centrin target by yeast-two-hybrid screening using both Homo sapiens centrin 2 (Hscen2) and Chlamydomonas reinhardtii centrin (Crcen). We identified a centrin-binding site within H...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28633435/mcm3ap-in-recessive-charcot-marie-tooth-neuropathy-and-mild-intellectual-disability
#16
Emil Ylikallio, Rosa Woldegebriel, Manuela Tumiati, Pirjo Isohanni, Monique M Ryan, Zornitza Stark, Maie Walsh, Sarah L Sawyer, Katrina M Bell, Alicia Oshlack, Paul J Lockhart, Mariia Shcherbii, Alejandro Estrada-Cuzcano, Derek Atkinson, Taila Hartley, Martine Tetreault, Inge Cuppen, W Ludo van der Pol, Ayse Candayan, Esra Battaloglu, Yesim Parman, Koen L I van Gassen, Marie-José H van den Boogaard, Kym M Boycott, Liisa Kauppi, Albena Jordanova, Tuula Lönnqvist, Henna Tyynismaa
Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function...
June 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28631420/expression-of-pten-long-mediated-by-crispr-cas9-can-repress-u87-cell-proliferation
#17
Na Fang, Tingxuan Gu, Yahui Wang, Shuzhen Wang, Fengling Wang, Yang An, Wenqiang Wei, Weijuan Zhang, Xiangqian Guo, Adil J Nazarali, Shaoping Ji
PTEN is a tumour suppressor that is frequently mutated in a variety of cancers. Hence, PTEN has significant potential as a therapeutic molecule. PTEN-long is an alternative translation variant, with an additional 173 amino acids added to the N-terminal of the canonical PTEN when CUG of the mRNA is utilized as the start codon. PTEN-long is secreted into serum and can re-enter cells throughout the body. One of the major barriers for gene therapy is to efficiently and specifically deliver DNA or RNA material to target cells...
June 19, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28627642/effect-of-retinoid-x-receptor-%C3%AE-nuclear-export-inhibition-on-apoptosis-of-neurons-in%C3%A2-vivo-and-in%C3%A2-vitro
#18
Yingchun Liu, Jiangguo Tang, Xiaoxiao Gao, Min Wang, Jie Shen, Xiaoqing You
Alzheimer's disease (AD), which is characte-rized by excessive apoptosis of neurons, is considered to be a global public health crisis. Retinoid-induced apoptosis is dependent on the orphan nuclear receptor Nur77, a transcription factor that is expressed predominantly in brain tissues. Nur77 nuclear export requires retinoid X receptor‑α (RXRα) as a carrier. However, the involvement of Nur77 in mediating β‑amyloid (Aβ)‑induced neuronal apoptosis has not yet been elucidated. The primary aim of the present study was to investigate the potential of Nur77 in Aβ‑induced neuron apoptosis, and to evaluate the effect of RXRα nuclear export inhibition on neuronal apoptosis...
August 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28592444/cellular-differentiation-state-modulates-the-mrna-export-activity-of-sr-proteins
#19
Valentina Botti, François McNicoll, Michaela C Steiner, Florian M Richter, Anfisa Solovyeva, Marius Wegener, Oliver D Schwich, Ina Poser, Kathi Zarnack, Ilka Wittig, Karla M Neugebauer, Michaela Müller-McNicoll
SR proteins function in nuclear pre-mRNA processing, mRNA export, and translation. To investigate their cellular dynamics, we developed a quantitative assay, which detects differences in nucleocytoplasmic shuttling among seven canonical SR protein family members. As expected, SRSF2 and SRSF5 shuttle poorly in HeLa cells but surprisingly display considerable shuttling in pluripotent murine P19 cells. Combining individual-resolution cross-linking and immunoprecipitation (iCLIP) and mass spectrometry, we show that elevated arginine methylation of SRSF5 and lower phosphorylation levels of cobound SRSF2 enhance shuttling of SRSF5 in P19 cells by modulating protein-protein and protein-RNA interactions...
July 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28591710/selective-inhibitors-of-nuclear-export-sine-compounds-block-proliferation-and-migration-of-triple-negative-breast-cancer-cells-by-restoring-expression-of-arrdc3
#20
Young Hwa Soung, Trinayan Kashyap, Thalia Nguyen, Garima Yadav, Hua Chang, Yosef Landesman, Jun Chung
Arrestin-related domain-containing protein-3 (ARRDC3) is one of 6 mammalian arrestins, which suppresses metastasis by inducing degradation of phosphorylated β2-adrenergic receptor (β2 AR) and integrin β4 (ITG β4). Our previous studies demonstrated that expression of ARRDC3 is epigentically silenced in Triple Negative Breast Cancer (TNBC) cells, and the forced expression of ARRDC3 significantly reduced the invasive potential of TNBC cells. In the current study, we found that Selective Inhibitors of Nuclear Export (SINE) compounds (KPT-185 and selinexor (KPT-330)) restore ARRDC3 expression in TNBC cell lines (MDA-MB-231 and MDA-MB-468) at both the mRNA and protein level in a dose and time course dependent manner...
May 18, 2017: Oncotarget
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