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Results: 11 to 20 of 131

Publication Record


The RNA Binding Protein Igf2bp1 Is Required for Zebrafish RGC Axon Outgrowth In Vivo.
Gaynes JA, Otsuna H, Campbell DS, Manfredi JP, Levine EM, Chien CB
(2015) PLoS One 10: e0134751
MeSH Terms: Actins, Animals, Axons, Gene Knockdown Techniques, RNA-Binding Proteins, Retinal Ganglion Cells, Zebrafish, Zebrafish Proteins
Show Abstract · Added November 2, 2015
Attractive growth cone turning requires Igf2bp1-dependent local translation of β-actin mRNA in response to external cues in vitro. While in vivo studies have shown that Igf2bp1 is required for cell migration and axon terminal branching, a requirement for Igf2bp1 function during axon outgrowth has not been demonstrated. Using a timelapse assay in the zebrafish retinotectal system, we demonstrate that the β-actin 3'UTR is sufficient to target local translation of the photoconvertible fluorescent protein Kaede in growth cones of pathfinding retinal ganglion cells (RGCs) in vivo. Igf2bp1 knockdown reduced RGC axonal outgrowth and tectal coverage and retinal cell survival. RGC-specific expression of a phosphomimetic Igf2bp1 reduced the density of axonal projections in the optic tract while sparing RGCs, demonstrating for the first time that Igf2bp1 is required during axon outgrowth in vivo. Therefore, regulation of local translation mediated by Igf2bp proteins may be required at all stages of axon development.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastric tumorigenesis.
Zhu S, Chen Z, Katsha A, Hong J, Belkhiri A, El-Rifai W
(2016) Oncogene 35: 1847-56
MeSH Terms: Alternative Splicing, Animals, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Dopamine and cAMP-Regulated Phosphoprotein 32, Gene Expression Regulation, Neoplastic, Humans, Hyaluronan Receptors, Mice, RNA-Binding Proteins, Serine-Arginine Splicing Factors, Signal Transduction, Stomach Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added September 28, 2015
CD44E is a frequently overexpressed variant of CD44 in gastric cancer. Mechanisms that regulate CD44 splicing and expression in gastric cancer remain unknown. Herein, we investigated the role of DARPP-32 (dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000) in promoting tumor growth through regulation of CD44 splicing. Using western blot and quantitative real-time PCR analysis, our results indicated that knockdown of endogenous DARPP-32 markedly reduces the expression of CD44 V8-V10 (CD44E). Using a quantitative splicing luciferase reporter system, we detected a significant increase in the reporter activity following DARPP-32 overexpression (P<0.001). Conversely, knocking down endogenous DARPP-32 significantly attenuated the splicing activity (P<0.001). Further experiments showed that DARPP-32 regulates the expression of SRp20 splicing factor and co-exists with it in the same protein complex. Inhibition of alternative splicing with digitoxin followed by immunoprecipitation and immunoblotting indicated that DARPP-32 has an important role in regulating SRp20 protein stability. The knockdown of endogenous DARPP-32 confirmed that DARPP-32 regulates the SRp20-dependent CD44E splicing. Using tumor xenograft mouse model, knocking down endogenous DARPP-32 markedly reduced SRp20 and CD44E protein levels with a decreased tumor growth. The reconstitution of SRp20 expression in these cells rescued tumor growth. In addition, we also demonstrated frequent co-overexpression and positive correlation of DARPP-32, SRp20 and CD44E expression levels in human gastric primary tumors. Our novel findings establish for the first time the role of DARPP-32 in regulating splicing factors in gastric cancer cells. The DARPP-32-SRp20 axis has a key role in regulating the CD44E splice variant that promotes gastric tumorigenesis.
0 Communities
1 Members
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15 MeSH Terms
Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome.
Gelfand BD, Wright CB, Kim Y, Yasuma T, Yasuma R, Li S, Fowler BJ, Bastos-Carvalho A, Kerur N, Uittenbogaard A, Han YS, Lou D, Kleinman ME, McDonald WH, Núñez G, Georgel P, Dunaief JL, Ambati J
(2015) Cell Rep 11: 1686-93
MeSH Terms: Alu Elements, Animals, Carrier Proteins, Caspase 1, DEAD-box RNA Helicases, Inflammasomes, Iron, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, RNA-Binding Proteins, Retinal Pigment Epithelium, Ribonuclease III
Show Abstract · Added January 26, 2016
Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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1 Members
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13 MeSH Terms
Detection of RNA-Protein Interactions Using Tethered RNA Affinity Capture.
Iioka H, Macara IG
(2015) Methods Mol Biol 1316: 67-73
MeSH Terms: Electrophoretic Mobility Shift Assay, Protein Binding, RNA, RNA-Binding Proteins
Show Abstract · Added April 10, 2018
Recent progress in large-scale nucleic acid analysis technology has revealed the presence of vast numbers of RNA species in cells, and extensive processing. To investigate the functions of these transcripts highly efficient methods are needed to analyze their interactions with RNA-binding proteins (RNBPs), and to understand the binding mechanisms. Many methods have been described to identify RNBPs, but none are wholly satisfactory, in part because RNAs are flexible macromolecules that adopt multiple conformations only some of which might bind to specific proteins. Here we describe a novel in vitro RNA-pull-down assay using tRNA scaffolded Streptavidin Aptamer (tRSA), to identify transcript specific RNA binding protein from mammalian cell lysates. The tRNA scaffold functions to stabilize the structure of the aptamer and the attached RNA, increasing the efficiency of the affinity purification.
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1 Members
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MeSH Terms
Loss of caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis.
Brown MF, Leibowitz BJ, Chen D, He K, Zou F, Sobol RW, Beer-Stolz D, Zhang L, Yu J
(2015) Cell Death Dis 6: e1729
MeSH Terms: Caspase 3, Cell Death, Colonic Neoplasms, DNA Damage, HCT116 Cells, HEK293 Cells, HT29 Cells, Humans, Nuclear Pore Complex Proteins, RNA-Binding Proteins, Transfection
Show Abstract · Added July 28, 2015
Caspase-3 is the best known executioner caspase in apoptosis. We generated caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU. C3KO cells showed intact apoptosis and activation of caspase-7 and -9, impaired processing of caspase-8, and induction of necrosis in response to DNA-damaging agents. This form of necrosis is associated with HMGB1 release and ROS production, and suppressed by genetic or pharmacological inhibition of RIP1, MLKL1, or caspase-8, but not inhibitors of pan-caspases or RIP3. 5-FU treatment led to the formation of a z-VAD-resistant pro-caspase-8/RIP1/FADD complex, which was strongly stabilized by caspase-3 KO. These data demonstrate a key role of caspase-3 in caspase-8 processing and suppression of DNA damage-induced necrosis, and provide a potentially novel way to chemosensitize cancer cells.
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1 Members
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11 MeSH Terms
The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers.
Qian J, Hassanein M, Hoeksema MD, Harris BK, Zou Y, Chen H, Lu P, Eisenberg R, Wang J, Espinosa A, Ji X, Harris FT, Rahman SM, Massion PP
(2015) Proc Natl Acad Sci U S A 112: 3469-74
MeSH Terms: Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Proliferation, Chromosomes, Human, Pair 3, DNA Copy Number Variations, Gene Expression Regulation, Neoplastic, Humans, Isoenzymes, Lung Neoplasms, Prognosis, Protein Kinase C, Proto-Oncogene Proteins, RNA, Messenger, RNA-Binding Proteins, Survival Analysis, Treatment Outcome
Show Abstract · Added February 16, 2016
Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.
0 Communities
1 Members
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17 MeSH Terms
Structural and functional insights into the N-terminus of Schizosaccharomyces pombe Cdc5.
Collier SE, Voehler M, Peng D, Ohi R, Gould KL, Reiter NJ, Ohi MD
(2014) Biochemistry 53: 6439-51
MeSH Terms: Binding Sites, Catalytic Domain, Cell Cycle Proteins, Gene Deletion, Models, Molecular, Mutant Proteins, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments, Protein Conformation, Protein Folding, Protein Interaction Domains and Motifs, Protein Stability, RNA Splicing, RNA, Double-Stranded, RNA, Fungal, RNA, Small Nuclear, RNA-Binding Proteins, Recombinant Proteins, Schizosaccharomyces pombe Proteins, Spliceosomes, Titrimetry
Show Abstract · Added January 20, 2015
The spliceosome is a dynamic macromolecular machine composed of five small nuclear ribonucleoparticles (snRNPs), the NineTeen Complex (NTC), and other proteins that catalyze the removal of introns mature to form the mature message. The NTC, named after its founding member Saccharomyces cerevisiae Prp19, is a conserved spliceosome subcomplex composed of at least nine proteins. During spliceosome assembly, the transition to an active spliceosome correlates with stable binding of the NTC, although the mechanism of NTC function is not understood. Schizosaccharomyces pombe Cdc5, a core subunit of the NTC, is an essential protein required for pre-mRNA splicing. The highly conserved Cdc5 N-terminus contains two canonical Myb (myeloblastosis) repeats (R1 and R2) and a third domain (D3) that was previously classified as a Myb-like repeat. Although the N-terminus of Cdc5 is required for its function, how R1, R2, and D3 each contribute to functionality is unclear. Using a combination of yeast genetics, structural approaches, and RNA binding assays, we show that R1, R2, and D3 are all required for the function of Cdc5 in cells. We also show that the N-terminus of Cdc5 binds RNA in vitro. Structural and functional analyses of Cdc5-D3 show that, while this domain does not adopt a Myb fold, Cdc5-D3 preferentially binds double-stranded RNA. Our data suggest that the Cdc5 N-terminus interacts with RNA structures proposed to be near the catalytic core of the spliceosome.
0 Communities
5 Members
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21 MeSH Terms
Nucleoporin FG domains facilitate mRNP remodeling at the cytoplasmic face of the nuclear pore complex.
Adams RL, Terry LJ, Wente SR
(2014) Genetics 197: 1213-24
MeSH Terms: Cloning, Molecular, Cytoplasm, DEAD-box RNA Helicases, Genetic Vectors, In Situ Hybridization, Fluorescence, Membrane Transport Proteins, Nuclear Pore Complex Proteins, Nuclear Proteins, Nucleocytoplasmic Transport Proteins, RNA, Messenger, RNA-Binding Proteins, Ribonucleoproteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added February 19, 2015
Directional export of messenger RNA (mRNA) protein particles (mRNPs) through nuclear pore complexes (NPCs) requires multiple factors. In Saccharomyces cerevisiae, the NPC proteins Nup159 and Nup42 are asymmetrically localized to the cytoplasmic face and have distinct functional domains: a phenylalanine-glycine (FG) repeat domain that docks mRNP transport receptors and domains that bind the DEAD-box ATPase Dbp5 and its activating cofactor Gle1, respectively. We speculated that the Nup42 and Nup159 FG domains play a role in positioning mRNPs for the terminal mRNP-remodeling steps carried out by Dbp5. Here we find that deletion (Δ) of both the Nup42 and Nup159 FG domains results in a cold-sensitive poly(A)+ mRNA export defect. The nup42ΔFG nup159ΔFG mutant also has synthetic lethal genetic interactions with dbp5 and gle1 mutants. RNA cross-linking experiments further indicate that the nup42ΔFG nup159ΔFG mutant has a reduced capacity for mRNP remodeling during export. To further analyze the role of these FG domains, we replaced the Nup159 or Nup42 FG domains with FG domains from other Nups. These FG "swaps" demonstrate that only certain FG domains are functional at the NPC cytoplasmic face. Strikingly, fusing the Nup42 FG domain to the carboxy-terminus of Gle1 bypasses the need for the endogenous Nup42 FG domain, highlighting the importance of proximal positioning for these factors. We conclude that the Nup42 and Nup159 FG domains target the mRNP to Gle1 and Dbp5 for mRNP remodeling at the NPC. Moreover, these results provide key evidence that character and context play a direct role in FG domain function and mRNA export.
Copyright © 2014 by the Genetics Society of America.
0 Communities
1 Members
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14 MeSH Terms
Normal telomere length maintenance in Saccharomyces cerevisiae requires nuclear import of the ever shorter telomeres 1 (Est1) protein via the importin alpha pathway.
Hawkins C, Friedman KL
(2014) Eukaryot Cell 13: 1036-50
MeSH Terms: Active Transport, Cell Nucleus, Amino Acid Sequence, Cell Nucleus, Molecular Sequence Data, Nuclear Localization Signals, Nucleocytoplasmic Transport Proteins, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomerase, Telomere Homeostasis, beta Karyopherins
Show Abstract · Added January 20, 2015
The Est1 (ever shorter telomeres 1) protein is an essential component of yeast telomerase, a ribonucleoprotein complex that restores the repetitive sequences at chromosome ends (telomeres) that would otherwise be lost during DNA replication. Previous work has shown that the telomerase RNA component (TLC1) transits through the cytoplasm during telomerase biogenesis, but mechanisms of protein import have not been addressed. Here we identify three nuclear localization sequences (NLSs) in Est1p. Mutation of the most N-terminal NLS in the context of full-length Est1p reduces Est1p nuclear localization and causes telomere shortening-phenotypes that are rescued by fusion with the NLS from the simian virus 40 (SV40) large-T antigen. In contrast to that of the TLC1 RNA, Est1p nuclear import is facilitated by Srp1p, the yeast homolog of importin α. The reduction in telomere length observed at the semipermissive temperature in a srp1 mutant strain is rescued by increased Est1p expression, consistent with a defect in Est1p nuclear import. These studies suggest that at least two nuclear import pathways are required to achieve normal telomere length homeostasis in yeast.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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1 Members
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12 MeSH Terms
Reovirus-mediated induction of ADAR1 (p150) minimally alters RNA editing patterns in discrete brain regions.
Hood JL, Morabito MV, Martinez CR, Gilbert JA, Ferrick EA, Ayers GD, Chappell JD, Dermody TS, Emeson RB
(2014) Mol Cell Neurosci 61: 97-109
MeSH Terms: Adenosine Deaminase, Age Factors, Analysis of Variance, Animals, Animals, Newborn, Body Weight, Brain, Gene Expression Regulation, Viral, Mice, Mice, Inbred C57BL, Protein Isoforms, RNA Editing, RNA, Messenger, RNA-Binding Proteins, Reoviridae
Show Abstract · Added January 20, 2015
Transcripts encoding ADAR1, a double-stranded, RNA-specific adenosine deaminase involved in the adenosine-to-inosine (A-to-I) editing of mammalian RNAs, can be alternatively spliced to produce an interferon-inducible protein isoform (p150) that is up-regulated in both cell culture and in vivo model systems in response to pathogen or interferon stimulation. In contrast to other tissues, p150 is expressed at extremely low levels in the brain and it is unclear what role, if any, this isoform may play in the innate immune response of the central nervous system (CNS) or whether the extent of editing for RNA substrates critical for CNS function is affected by its induction. To investigate the expression of ADAR1 isoforms in response to viral infection and subsequent alterations in A-to-I editing profiles for endogenous ADAR targets, we used a neurotropic strain of reovirus to infect neonatal mice and quantify A-to-I editing in discrete brain regions using a multiplexed, high-throughput sequencing strategy. While intracranial injection of reovirus resulted in a widespread increase in the expression of ADAR1 (p150) in multiple brain regions and peripheral organs, significant changes in site-specific A-to-I conversion were quite limited, suggesting that steady-state levels of p150 expression are not a primary determinant for modulating the extent of editing for numerous ADAR targets in vivo.
Copyright © 2014 Elsevier Inc. All rights reserved.
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2 Members
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15 MeSH Terms