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Glutamine AND beta cell proliferation

Arnulf H Koeppen, R Liane Ramirez, Alyssa B Becker, Joseph E Mazurkiewicz
INTRODUCTION: Dorsal root ganglia (DRG) are highly vulnerable to frataxin deficiency in Friedreich ataxia (FA), an autosomal recessive disease due to pathogenic homozygous guanine-adenine-adenine trinucleotide repeat expansions in intron 1 of the FXN gene (chromosome 9q21.11). An immunohistochemical and immunofluorescence study of DRG in 15 FA cases and 12 controls revealed that FA causes major primary changes in satellite cells and inflammatory destruction of neurons. A panel of antibodies was used to reveal the cytoplasm of satellite cells (glutamine synthetase, S100, metabotropic glutamate receptors 2/3, excitatory amino acid transporter 1, ATP-sensitive inward rectifier potassium channel 10, and cytosolic ferritin), gap junctions (connexin 43), basement membranes (laminin), mitochondria (ATP synthase subunit beta and frataxin), and monocytes (CD68 and IBA1)...
2016: Acta Neuropathologica Communications
Honey Modi, Marion Cornu, Bernard Thorens
IGF2 is an autocrine ligand for the beta cell IGF1R receptor and GLP-1 increases the activity of this autocrine loop by enhancing IGF1R expression, a mechanism that mediates the trophic effects of GLP-1 on beta cell mass and function. Here, we investigated the regulation of IGF2 biosynthesis and secretion. We showed that glutamine rapidly and strongly induced IGF2 mRNA translation using reporter constructs transduced in MIN6 cells and primary islet cells. This was followed by rapid secretion of IGF2 via the regulated pathway, as revealed by the presence of mature IGF2 in insulin granule fractions and by inhibition of secretion by nimodipine and diazoxide...
November 14, 2014: Journal of Biological Chemistry
Zongwei Li, Yingying Wang, Haili Wu, Lichao Zhang, Peng Yang, Zhuoyu Li
To support the high rates of proliferation, cancer cells undergo the metabolic reprogramming: aerobic glycolysis and glutamine addiction. Though glucose regulated protein 78 (GRP78) is a glucose-sensing protein and frequently highly expressed in tumor cells, its roles in glucose and glutamine metabolic regulation remain poorly unknown. We report here that glucose deficiency-induced GRP78 enhances β-catenin signaling and consequently promotes its downstream c-Myc-mediated glutamine metabolism in colorectal cancer cells...
July 30, 2014: Oncotarget
Jung Min Lee, Jing Yang, Pippa Newell, Sucha Singh, Anil Parwani, Scott L Friedman, Kari Nichole Nejak-Bowen, Satdarshan P Monga
β-Catenin signaling is implicated in hepatocellular carcinoma (HCC), although its role in inflammation, fibrosis, and proliferation is unclear. Commercially available HCC tissue microarray (TMA) of 89 cases was assessed for β-catenin, one of its transcriptional targets glutamine synthetase (GS), proliferation (PCNA), inflammation (CD45), and fibrosis (Sirius Red). HCC cells transfected with wild-type (WT) or mutant-β-catenin were evaluated for β-catenin-T cell factor transactivation by TOPFlash reporter activity and expression of certain targets...
February 1, 2014: Cancer Letters
Shi-Hai Xia, Xiao-Hui Xiang, Kai Chen, Wei Xu
AIM: To determine the effects of BN52021 on platelet-activating factor receptor (PAFR) signaling molecules under lipopolysaccharide (LPS)-induced inflammatory conditions in MS1 cells. METHODS: MS1 cells (a mouse pancreatic islet endothelial cell line) were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 2 mmol/L glutamine and 100 μg/mL penicillin/streptomycin in 5% CO2 at 37 °C. After growth to confluency in media, the cells were processed for subsequent studies...
July 7, 2013: World Journal of Gastroenterology: WJG
Evan Delgado, Raman Bahal, Jing Yang, Jung M Lee, Danith H Ly, Satdarshan P S Monga
Hepatocellular cancer (HCC) is the third cause of death by cancer worldwide. In the current study we target β- catenin, an oncogene mutated and constitutively active in 20-30% of HCCs, via a novel, cell permeable gamma guanidine-based peptide nucleic acid (γGPNA) antisense oligonucleotide designed against either the transcription or the translation start site of the human β-catenin gene. Using TOPflash, a luciferase reporter assay, we show that γGPNA targeting the transcription start site showed more robust activity against β-catenin activity in liver tumor cells that harbor β-catenin gene mutations (HepG2 & Snu-449)...
October 2013: Current Cancer Drug Targets
Daiane Cattani, Paola Bez Goulart, Vera Lúcia de Liz Oliveira Cavalli, Elisa Winkelmann-Duarte, André Quincozes Dos Santos, Paula Pierozan, Daniela Fraga de Souza, Viviane Mara Woehl, Marilda C Fernandes, Fátima Regina Mena Barreto Silva, Carlos Alberto Gonçalves, Regina Pessoa-Pureur, Ariane Zamoner
Congenital hypothyroidism is associated with delay in cell migration and proliferation in brain tissue, impairment of synapse formation, misregulation of neurotransmitters, hypomyelination and mental retardation. However, the mechanisms underlying the neuropsychological deficits observed in congenital hypothyroidism are not completely understood. In the present study we proposed a mechanism by which hypothyroidism leads to hippocampal neurotoxicity. Congenital hypothyroidism induces c-Jun-N-terminal kinase (JNK) pathway activation leading to hyperphosphorylation of the glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits from hippocampal astrocytes and neurons, respectively...
August 15, 2013: Molecular and Cellular Endocrinology
Jan de Weille, Christine Fabre, Camille Gaven, Norbert Bakalara
Oxysterols possess anti-proliferative properties that may be used with much effect in the treatment of cancer. We have demonstrated previously that 7 beta-hydroxycholesterol (7b-HC) provokes both metabolic stress, as witnessed by AMPK activation, and changes in lipid raft composition in C6 glioblastoma cells. These observations suggested that glycolysis might have been changed. Here we will show that 7b-HC increases cell cycle time and that it changes the affinity of pyruvate kinase to its substrate, phosphoenol pyruvate...
July 1, 2013: Biochemical Pharmacology
Hammou Oubrahim, Allison Wong, Brenda A Wilson, P Boon Chock
Pasteurella multocida toxin (PMT) is a potent mitogen known to activate several signaling pathways via deamidation of a conserved glutamine residue in the α subunit of heterotrimeric G-proteins. However, the detailed mechanism behind mitogenic properties of PMT is unknown. Herein, we show that PMT induces protein synthesis, cell migration, and proliferation in serum-starved Swiss 3T3 cells. Concomitantly PMT induces phosphorylation of ribosomal S6 kinase (S6K1) and its substrate, ribosomal S6 protein (rpS6), in quiescent 3T3 cells...
January 25, 2013: Journal of Biological Chemistry
Marion Walser, Maria Teresa Samà, Ruth Wickelgren, Maria Aberg, Mohammad Bohlooly-Y, Bob Olsson, Jan Törnell, Jörgen Isgaard, N David Aberg
GH therapy improves hippocampal functions mainly via circulating IGF1. However, the roles of local GH and IGF1 expression are not well understood. We investigated whether transgenic (TG) overexpression in the adult brain of bovine GH (bGH) under the control of the glial fibrillary acidic protein (GFAP) promoter affected cellular proliferation and the expression of transcripts known to be induced by systemic GH in the hippocampus. Cellular proliferation was examined by 5-bromo-2'-deoxyuridine immunohistochemistry...
November 2012: Journal of Endocrinology
Holly Meredith Kolenda-Roberts, Nancy Harris, Emily Singletary, Jerry F Hardisty
Twenty-eight spontaneously occurring glial tumors (previously diagnosed as astrocytomas, oligodendrogliomas, and gliomas) and eleven granular cell tumors (GCTs) were selected for evaluation using a panel of immunohistochemistry (IHC) stains (Ricinus communis agglutinin type 1 [RCA-1], ionized calcium-binding adapter molecule 1 [Iba-1], OX-6/major immunohistocompatibility complex class II, oligodendrocytes transcription factor 2 [Olig2], glial fibrillary acidic protein [GFAP], S100 beta, glutamine synthetase, neurofilament, proliferating cell nuclear antigen)...
January 2013: Toxicologic Pathology
Prince Kwaku Awuah, Byung Han Rhieu, Sucha Singh, Amalea Misse, Satdarshan P S Monga
Hepatocellular Carcinoma (HCC) is the fifth most common cancer worldwide. β-Catenin, the central orchestrator of the canonical Wnt pathway and a known oncogene is paramount in HCC pathogenesis. Administration of phenobarbital (PB) containing water (0.05% w/v) as tumor promoter following initial injected intraperitoneal (IP) diethylnitrosamine (DEN) injection (5 µg/gm body weight) as a tumor inducer is commonly used model to study HCC in mice. Herein, nine fifteen-day male β-catenin knockout mice (KO) and fifteen wild-type littermate controls (WT) underwent DEN/PB treatment and were examined for hepatic tumorigenesis at eight months...
2012: PloS One
Umesh T Sankpal, Steven Goodison, Maen Abdelrahim, Riyaz Basha
Transcription factors are proteins that regulate gene expression by binding to specific DNA sequences within gene promoter regions. Specificity protein (Sp) family transcription factors play a critical role in various cellular processes and have been shown to be associated with tumorigenesis. The Sp family consists of several members that contain a highly conserved DNA-binding domain composed of three zinc fingers at the C-terminus and serine/threonine- and glutamine-rich transactivation domains at the N-terminal...
September 2011: Medicinal Chemistry
Philip M Brown, James D Hutchison, Julie C Crockett
Osteoblasts in vitro differentiate from a proliferating to a mineralizing phenotype upon transfer to a medium rich in beta-glycerophosphate and ascorbic acid. The nutritional requirements of the cells at different stages of this differentiation process are not known. In other cell types, nutritional supplementation during surgery can improve the outcome in terms of speed of patient recovery and prognosis. There is therefore the potential for supplementation at the site of fracture repair or bone grafting with critical osteoblast nutritional factors to potentially accelerate healing...
December 2011: Calcified Tissue International
S Tardito, M Chiu, J Uggeri, A Zerbini, F Da Ros, V Dall'Asta, G Missale, O Bussolati
Selected oncogenic mutations support unregulated growth enhancing glutamine availability but increasing the dependence of tumor cells on the amino acid. Data from literature indicate that a subset of HepatoCellular Carcinomas (HCC) is characterized by mutations of β-catenin and overexpression of Glutamine Synthetase (GS). To assess if this phenotype may constitute an example of glutamine addiction, we treated four human HCC lines with the enzyme L-Asparaginase (ASNase), a glutaminolytic drug. ASNase had a significant antiproliferative effect only in the β-catenin mutated HepG2 cells, which were partially rescued by the anaplerotic intermediates pyruvate and α-ketoglutarate...
October 2011: Current Cancer Drug Targets
Sandra Schreiber, Benjamin Rignall, Albert Braeuning, Philip Marx-Stoelting, Thomas Ott, Albrecht Buchmann, Seddik Hammad, Jan G Hengstler, Michael Schwarz, Christoph Köhle
The gene CTNNB1 encoding β-catenin is mutated in about 30% of hepatocellular carcinoma, generally often combined with other genetic alterations. In transgenic mice, it has been shown that activation of β-catenin in more than 70% of all hepatocytes causes immediate proliferation leading to hepatomegaly. In this study we established a novel mouse model where β-catenin is activated only in individual, dispersed hepatocytes. Hepatocyte-specific expression of activated point-mutated β-catenin (human β-catenin(S33Y)) was established using the Cre/loxP system...
October 2011: Journal of Molecular Histology
Andreas Schmidt, Albert Braeuning, Peter Ruck, Guido Seitz, Sorin Armeanu-Ebinger, Joerg Fuchs, Steven W Warmann, Michael Schwarz
Carcinogenesis is often linked to aberrant activation of Wnt/β-catenin signalling, in many cases caused by activating CTNNB1 mutations (encoding β-catenin). Recently, β-catenin was established as a decisive regulator of hepatic glutamine synthetase (GS) and cytochrome P450 (CYP) expression in mouse hepatocarcinogenesis. This study was aimed to analyse the connection of β-catenin signalling and GS/CYP expression in human paediatric tumours. Samples from 23 paediatric tumours were analysed for activating mutations in CTNNB1...
March 15, 2011: Toxicology
Michael D Thompson, Mohd Jamal Dar, Satdarshan P S Monga
BACKGROUND & AIMS: Pegylated-Interferon-α2a (peg-IFN), a first line therapy for Hepatitis C virus (HCV) patients, also impacts the recurrence of hepatocellular carcinoma (HCC). The activation of the Wnt pathway due to β-catenin gene mutations contributes to the development of a significant subset of HCC. Herein, we explored the effect of peg-IFN on Wnt/β-catenin signaling in vitro and in vivo. METHODS: Multiple human hepatoma cell lines were treated with Peg-IFN to assess its effect on the Wnt pathway and the mechanisms involved...
March 2011: Journal of Hepatology
Kari N Nejak-Bowen, Michael D Thompson, Sucha Singh, William C Bowen, Mohd Jamal Dar, Jaspal Khillan, Chunsun Dai, Satdarshan P S Monga
UNLABELLED: The Wnt/beta-catenin pathway is implicated in the pathogenesis of hepatocellular cancer (HCC). We developed a transgenic mouse (TG) in the FVB strain that overexpresses Ser45-mutated-beta-catenin in hepatocytes to study the effects on liver regeneration and cancer. In the two independent TG lines adult mice show elevated beta-catenin at hepatocyte membrane with no increase in the Wnt pathway targets cyclin-D1 or glutamine synthetase. However, TG hepatocytes upon culture exhibit a 2-fold increase in thymidine incorporation at day 5 (D5) when compared to hepatocytes from wildtype FVB mice (WT)...
May 2010: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Andrew Philp, Joaquin Perez-Schindler, Charlotte Green, D Lee Hamilton, Keith Baar
Sodium pyruvate can increase mitochondrial biogenesis in C2C12 myoblasts in a peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha)-independent manner. The present study examined the effect of 72-h treatment with sodium pyruvate (5-50 mM) or sodium chloride (50 mM) as an osmotic control on the regulation of mitochondrial substrate metabolism and biogenesis in C2C12 myotubes. Pyruvate (50 mM) increased the levels of fatty acid oxidation enzymes (CD36, 61%, and beta-oxidative enzyme 3-hydroxyacyl-CoA dehydrogenase, 54%) and the expression of cytochrome-c oxidase subunit I (220%) and cytochrome c (228%), consistent with its previous described role as a promoter of mitochondrial biogenesis...
August 2010: American Journal of Physiology. Cell Physiology
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