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Rikard G Fred, Syrina Mehrabi, Christopher M Adams, Nils Welsh
OBJECTIVES: Insulin expression is highly controlled on the posttranscriptional level. The RNA binding proteins (RBPs) responsible for this result are still largely unknown. METHODS AND RESULTS: To identify RBPs that bind to insulin mRNA we performed mass spectrometry analysis on proteins that bound synthetic oligonucloetides mimicing the 5'- and the 3'-untranslated regions (UTRs) of rat and human insulin mRNA in vitro. We observed that the RBPs heterogeneous nuclear ribonucleoprotein (hnRNP) U, polypyrimidine tract binding protein (PTB), hnRNP L and T-cell restricted intracellular antigen 1-related protein (TIA-1-related protein; TIAR) bind to insulin mRNA sequences, and that the in vitro binding affinity of these RBPs changed when INS-1 cells were exposed to glucose, 3-isobutyl-1-methylxanthine (IBMX) or nitric oxide...
September 2016: Heliyon
Caleb Sutherland, Yunxi Cui, Hanbin Mao, Laurence H Hurley
MYC is overexpressed in many different cancer types and is an intensively studied oncogene because of its contributions to tumorigenesis. The regulation of MYC is complex, and the NHE III1 and FUSE elements rely upon noncanonical DNA structures and transcriptionally induced negative superhelicity. In the NHE III1 only the G-quadruplex has been extensively studied, whereas the role of the i-motif, formed on the opposite C-rich strand, is much less understood. We demonstrate here that the i-motif is formed within the 4CT element and is recognized by hnRNP K, which leads to a low level of transcription activation...
October 11, 2016: Journal of the American Chemical Society
Mohammad Nazim, Akio Masuda, Mohammad Alinoor Rahman, Farhana Nasrin, Jun-Ichi Takeda, Kenji Ohe, Bisei Ohkawara, Mikako Ito, Kinji Ohno
Acetylcholinesterase (AChE), encoded by the ACHE gene, hydrolyzes the neurotransmitter acetylcholine to terminate synaptic transmission. Alternative splicing close to the 3' end generates three distinct isoforms of AChET, AChEH and AChER We found that hnRNP H binds to two specific G-runs in exon 5a of human ACHE and activates the distal alternative 3' splice site (ss) between exons 5a and 5b to generate AChET Specific effect of hnRNP H was corroborated by siRNA-mediated knockdown and artificial tethering of hnRNP H...
September 19, 2016: Nucleic Acids Research
Erin G Conlon, Lei Lu, Aarti Sharma, Takashi Yamazaki, Timothy Tang, Neil A Shneider, James L Manley
An expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate with proteins, but whether this occurs and contributes to disease is unknown. Here we show first that the protein that predominantly associates with GGGGCC repeat RNA in vitro is the splicing factor hnRNP H, and that this interaction is linked to G-Q formation...
September 13, 2016: ELife
Bruno Palhais, Maja Dembic, Rugivan Sabaratnam, Kira S Nielsen, Thomas Koed Doktor, Gitte Hoffmann Bruun, Brage Storstein Andresen
Fabry disease is an X-linked recessive inborn disorder of the glycosphingolipid metabolism, caused by total or partial deficiency of the lysosomal α-galactosidase A enzyme due to mutations in the GLA gene. The prevalent c.639+919 G>A mutation in GLA leads to pathogenic insertion of a 57bp pseudoexon sequence from intron 4, which is responsible for the cardiac variant phenotype. In this study we investigate the splicing regulatory mechanism leading to GLA pseudoexon activation. Splicing analysis of GLA minigenes revealed that pseudoexon activation is influenced by cell-type...
August 27, 2016: Molecular Genetics and Metabolism
Erica J Hutchins, Jamie L Belrose, Ben G Szaro
hnRNP K is a highly conserved nucleocytoplasmic shuttling protein, which associates with RNAs through synergistic binding via its three KH domains. hnRNP K is required for proper nuclear export and translational control of its mRNA targets, and these processes are controlled by hnRNP K's movement between subcellular compartments. Whereas the nuclear export and localization of hnRNP K that is associated with mRNP complexes has been well studied, the trafficking of hnRNP K that is unbound to mRNA has yet to be elucidated...
September 16, 2016: Biochemical and Biophysical Research Communications
Anne Molitor, David Latrasse, Matthias Zytnicki, Philippe Andrey, Nicole Houba-Hérin, Mélanie Hachet, Christophe Battail, Stefania Del Prete, Adriana Alberti, Hadi Quesneville, Valerie Gaudin
LHP1-INTERACTING FACTOR2 (LIF2), a heterogeneous nuclear ribonucleoprotein involved in Arabidopsis thaliana cell fate and stress responses, interacts with LIKE HETEROCHROMATIN PROTEIN1 (LHP1), a Polycomb Repressive Complex1 (PRC1) subunit. To investigate LIF2-LHP1 functional interplay, we mapped their genome-wide distributions in wild-type, lif2, and lhp1 backgrounds, under standard and stress conditions. Interestingly, LHP1-targeted regions form local clusters, suggesting an underlying functional organization of the plant genome...
August 5, 2016: Plant Cell
Samuel Liebel, Sonia Regina Grötzner, Daniele Dietrich Moura Costa, Marco Antônio Ferreira Randi, Ciro Alberto de Oliveira Ribeiro, Francisco Filipak Neto
Human hepatoma cells (HepG2) were exposed to purified cylindrospermopsin (CYN), a potent toxicant for eukaryotic cells produced by several cyanobacteria. Exposure to 10 μg l(-1) of CYN for 24 h resulted in alteration of expression of 48 proteins, from which 26 were identified through mass spectrometry. Exposure to 100 μg l(-1) of CYN for 24 h affected nuclear area and actin filaments intensity, which can be associated with cell proliferation and toxicity. The proteins are implicated in different biological processes: protein folding, xenobiotic efflux, antioxidant defense, energy metabolism and cell anabolism, cell signaling, tumorigenic potential, and cytoskeleton structure...
August 5, 2016: Toxicology Mechanisms and Methods
Benjamin Kolisnyk, Mohammed A Al-Onaizi, Jason Xu, Gustavo M Parfitt, Valeriy G Ostapchenko, Geula Hanin, Hermona Soreq, Marco A M Prado, Vania F Prado
UNLABELLED: Cholinergic vulnerability, characterized by loss of acetylcholine (ACh), is one of the hallmarks of Alzheimer's disease (AD). Previous work has suggested that decreased ACh activity in AD may contribute to pathological changes through global alterations in alternative splicing. This occurs, at least partially, via the regulation of the expression of a critical protein family in RNA processing, heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins. These proteins regulate several steps of RNA metabolism, including alternative splicing, RNA trafficking, miRNA export, and gene expression, providing multilevel surveillance in RNA functions...
June 8, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Michael M Kunze, Fabienne Benz, Thilo F Brauß, Sebastian Lampe, Julia E Weigand, Johannes Braun, Florian M Richter, Ilka Wittig, Bernhard Brüne, Tobias Schmid
Translation is an energy-intensive process and tightly regulated. Generally, translation is initiated in a cap-dependent manner. Under stress conditions, typically found within the tumor microenvironment in association with e.g. nutrient deprivation or hypoxia, cap-dependent translation decreases, and alternative modes of translation initiation become more important. Specifically, internal ribosome entry sites (IRES) facilitate translation of specific mRNAs under otherwise translation-inhibitory conditions...
July 2016: Biochimica et Biophysica Acta
Anne Cammas, Magali Lacroix-Triki, Sandra Pierredon, Morgane Le Bras, Jason S Iacovoni, Marie-Paule Teulade-Fichou, Gilles Favre, Henri Roché, Thomas Filleron, Stefania Millevoi, Stéphan Vagner
The expression and role of RNA binding proteins (RBPs) controlling mRNA translation during tumor progression remains largely uncharacterized. Analysis by immunohistochemistry of the expression of hnRNP A1, hnRNPH, RBM9/FOX2, SRSF1/ASF/SF2, SRSF2/SC35, SRSF3/SRp20, SRSF7/9G8 in breast tumors shows that the expression of hnRNP A1, but not the other tested RBPs, is associated with metastatic relapse. Strikingly, hnRNP A1, a nuclear splicing regulator, is also present in the cytoplasm of tumor cells of a subset of patients displaying exceedingly worse prognosis...
March 29, 2016: Oncotarget
Taiyo Otoshi, Tomoaki Tanaka, Kazuya Morimoto, Tatsuya Nakatani
Heterogeneous nuclear ribonucleoprotein (hnRNP) K is a part of the ribonucleoprotein complex which regulates diverse biological events. While overexpression of hnRNP K has been shown to be related to tumorigenesis in several cancers, both the expression patterns and biological mechanisms of hnRNP K in renal cell carcinoma (RCC) cells remain unclear. In this study, we showed that hnRNP K protein was strongly expressed in selected RCC cell lines (ACHN, A498, Caki-1, 786-0), and knock-down of hnRNP K expression by siRNA induced cell growth inhibition and apoptosis...
2015: PloS One
Kathryn R Williams, Damian S McAninch, Snezana Stefanovic, Lei Xing, Megan Allen, Wenqi Li, Yue Feng, Mihaela Rita Mihailescu, Gary J Bassell
Posttranscriptional regulation of gene expression by mRNA-binding proteins is critical for neuronal development and function. hnRNP-Q1 is an mRNA-binding protein that regulates mRNA processing events, including translational repression. hnRNP-Q1 is highly expressed in brain tissue, suggesting a function in regulating genes critical for neuronal development. In this study, we have identified Growth-associated protein 43 (Gap-43) mRNA as a novel target of hnRNP-Q1 and have demonstrated that hnRNP-Q1 represses Gap-43 mRNA translation and consequently GAP-43 function...
February 1, 2016: Molecular Biology of the Cell
Poulami Talukder, Shengxi Chen, Basab Roy, Petro Yakovchuk, Michelle M Spiering, Mohammad P Alam, Manikandadas M Madathil, Chandrabali Bhattacharya, Stephen J Benkovic, Sidney M Hecht
Described herein are the syntheses and photophysical characterization of three novel cyanotryptophans, and their efficient incorporation into proteins as fluorescent probes. Photophysical characteristics indicated that each was significantly brighter and red-shifted in fluorescence emission relative to tryptophan. Each analogue was used to activate a suppressor tRNA transcript and was incorporated with good efficiency into two different positions (Trp22 and Trp74) of Escherichia coli dihydrofolate reductase (ecDHFR)...
December 29, 2015: Biochemistry
Michal Mikula, Tymon Rubel, Jakub Karczmarski, Malgorzata Statkiewicz, Karol Bomsztyk, Jerzy Ostrowski
BACKGROUND: Protein immunoprecipitation (IP) coupled with MS provides means to interrogate protein complexes and their posttranslational modifications (PTMs). In a typical protein IP assay antibodies are conjugated to protein A/G beads requiring large amounts of antibodies, tube transfers and centrifugations. RESULTS: As an alternative, we present Matrix-IP, beads-free microplate-based platform with surface-immobilized antibodies. Assay utilizes standard 96-well polypropylene PCR plates that are laboratory-fabricated with UV-C light and then protein A/G coated prior to IP reaction...
2015: Proteome Science
Jun Qiu, Jinggong Liu, Shuobin Chen, Tian-Miao Ou, Jia-Heng Tan, Lian-Quan Gu, Zhi-Shu Huang, Ding Li
The promoter of hnRNP K oncogene was found to contain a G/C-rich sequence on the same DNA strand, which can form interconvertible G-quadruplex, i-motif, and hairpin structures. Protein CNBP could bind and stabilize the G-quadruplex, inducing transformation of the hairpin into the G-quadruplex, resulting in down-regulation of hnRNP K transcription. In contrast, Corticosterone could bind and stabilize the hairpin, inducing transformation of the G-quadruplex into the hairpin, resulting in up-regulation of hnRNP K gene transcription...
September 18, 2015: Organic Letters
Kentaro Ikeda, Shinji Kamisuki, Shoko Uetake, Akihito Mizusawa, Nozomi Ota, Tatsuki Sasaki, Senko Tsukuda, Tomoe Kusayanagi, Yoichi Takakusagi, Kengo Morohashi, Takao Yamori, Shingo Dan, Isamu Shiina, Fumio Sugawara
Ridaifen-G (RID-G), a tamoxifen analog that we previously synthesized, has potent growth inhibitory activity against various cancer cell lines. Tamoxifen is an anticancer drug known to act on an estrogen receptor (ER) and other proteins. However, our previous studies interestingly suggested that the mechanism of action of RID-G was different from that of tamoxifen. In order to investigate the molecular mode of action of RID-G, we developed a novel chemical genetic approach that combined a phage display screen with a statistical analysis of drug potency and gene expression profiles in thirty-nine cancer cell lines...
September 15, 2015: Bioorganic & Medicinal Chemistry
Mohammad Alinoor Rahman, Yoshiteru Azuma, Farhana Nasrin, Jun-ichi Takeda, Mohammad Nazim, Khalid Bin Ahsan, Akio Masuda, Andrew G Engel, Kinji Ohno
The catalytic subunits of acetylcholinesterase (AChE) are anchored in the basal lamina of the neuromuscular junction using a collagen-like tail subunit (ColQ) encoded by COLQ. Mutations in COLQ cause endplate AChE deficiency. An A-to-G mutation predicting p.E415G in COLQ exon 16 identified in a patient with endplate AChE deficiency causes exclusive skipping of exon 16. RNA affinity purification, mass spectrometry, and siRNA-mediated gene knocking down disclosed that the mutation disrupts binding of a splicing-enhancing RNA-binding protein, SRSF1, and de novo gains binding of a splicing-suppressing RNA-binding protein, hnRNP H...
2015: Scientific Reports
L Courteau, J Crasto, G Hassanzadeh, S D Baird, J Hodgins, U Liwak-Muir, G Fung, H Luo, D F Stojdl, R A Screaton, M Holcik
Subcellular localization of RNA-binding proteins is a key determinant of their ability to control RNA metabolism and cellular stress response. Using an RNAi-based kinome-wide screen, we identified hexokinase 2 (HK2) as a regulator of the cytoplasmic accumulation of hnRNP A1 in response to hypertonic stress and human rhinovirus infection (HRV). We show that inhibition of HK2 expression or pharmacological inhibition of HK2 activity blocks the cytoplasmic accumulation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), restores expression of B-cell lymphoma-extra large (Bcl-xL), and protects cells against hypertonic stress-induced apoptosis...
2015: Cell Death & Disease
Chao-Sheng Lo, Yixuan Shi, Shiao-Ying Chang, Shaaban Abdo, Isabelle Chenier, Janos G Filep, Julie R Ingelfinger, Shao-Ling Zhang, John S D Chan
AIMS/HYPOTHESIS: We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. METHODS: Adult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls...
October 2015: Diabetologia
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