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α-Difluoromethylornithine reduces gastric carcinogenesis by causing mutations in .
Sierra JC, Suarez G, Piazuelo MB, Luis PB, Baker DR, Romero-Gallo J, Barry DP, Schneider C, Morgan DR, Peek RM, Gobert AP, Wilson KT
(2019) Proc Natl Acad Sci U S A 116: 5077-5085
MeSH Terms: Animals, Bacterial Proteins, Carcinogenesis, DNA Damage, Eflornithine, Gene Deletion, Gene Rearrangement, Gerbillinae, Helicobacter pylori, Male, Mutation, Oxidative Stress, RNA, Messenger, Stomach Neoplasms, Virulence
Show Abstract · Added February 26, 2019
Infection by is the primary cause of gastric adenocarcinoma. The most potent virulence factor is cytotoxin-associated gene A (CagA), which is translocated by a type 4 secretion system (T4SS) into gastric epithelial cells and activates oncogenic signaling pathways. The gene encodes for a key component of the T4SS and can undergo gene rearrangements. We have shown that the cancer chemopreventive agent α-difluoromethylornithine (DFMO), known to inhibit the enzyme ornithine decarboxylase, reduces -mediated gastric cancer incidence in Mongolian gerbils. In the present study, we questioned whether DFMO might directly affect pathogenicity. We show that output strains isolated from gerbils treated with DFMO exhibit reduced ability to translocate CagA in gastric epithelial cells. Further, we frequently detected genomic modifications in the middle repeat region of the gene of output strains from DFMO-treated animals, which were associated with alterations in the CagY protein. Gerbils did not develop carcinoma when infected with a DFMO output strain containing rearranged or the parental strain in which the wild-type was replaced by with DFMO-induced rearrangements. Lastly, we demonstrate that in vitro treatment of by DFMO induces oxidative DNA damage, expression of the DNA repair enzyme MutS2, and mutations in , demonstrating that DFMO directly affects genomic stability. Deletion of abrogated the ability of DFMO to induce rearrangements directly. In conclusion, DFMO-induced oxidative stress in leads to genomic alterations and attenuates virulence.
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15 MeSH Terms
Genetic loss of GluN2B in D1-expressing cell types enhances long-term cocaine reward and potentiation of thalamo-accumbens synapses.
Joffe ME, Turner BD, Delpire E, Grueter BA
(2018) Neuropsychopharmacology 43: 2383-2389
MeSH Terms: Animals, Cocaine, Gene Deletion, Locomotion, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nucleus Accumbens, Receptors, Dopamine D1, Receptors, N-Methyl-D-Aspartate, Reward, Thalamus
Show Abstract · Added April 2, 2019
Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories.
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Glycine -methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates.
Hughey CC, Trefts E, Bracy DP, James FD, Donahue EP, Wasserman DH
(2018) J Biol Chem 293: 11944-11954
MeSH Terms: Animals, Carbon, Citric Acid Cycle, Energy Metabolism, Fatty Liver, Gene Deletion, Gluconeogenesis, Glucose, Glycine N-Methyltransferase, Liver, Male, Metabolic Flux Analysis, Methionine, Mice, Mice, Knockout, S-Adenosylmethionine
Show Abstract · Added March 26, 2019
Glycine -methyltransferase (GNMT) is the most abundant liver methyltransferase regulating the availability of the biological methyl donor, -adenosylmethionine (SAM). Moreover, GNMT has been identified to be down-regulated in hepatocellular carcinoma (HCC). Despite its role in regulating SAM levels and association of its down-regulation with liver tumorigenesis, the impact of reduced GNMT on metabolic reprogramming before the manifestation of HCC has not been investigated in detail. Herein, we used H/C metabolic flux analysis in conscious, unrestrained mice to test the hypothesis that the absence of GNMT causes metabolic reprogramming. GNMT-null (KO) mice displayed a reduction in blood glucose that was associated with a decline in both hepatic glycogenolysis and gluconeogenesis. The reduced gluconeogenesis was due to a decrease in liver gluconeogenic precursors, citric acid cycle fluxes, and anaplerosis and cataplerosis. A concurrent elevation in both hepatic SAM and metabolites of SAM utilization pathways was observed in the KO mice. Specifically, the increase in metabolites of SAM utilization pathways indicated that hepatic polyamine synthesis and catabolism, transsulfuration, and lipogenesis pathways were increased in the KO mice. Of note, these pathways utilize substrates that could otherwise be used for gluconeogenesis. Also, this metabolic reprogramming occurs before the well-documented appearance of HCC in GNMT-null mice. Together, these results indicate that GNMT deletion promotes a metabolic shift whereby nutrients are channeled away from glucose formation toward pathways that utilize the elevated SAM.
© 2018 Hughey et al.
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MeSH Terms
HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis.
Choby JE, Grunenwald CM, Celis AI, Gerdes SY, DuBois JL, Skaar EP
(2018) MBio 9:
MeSH Terms: Aldehyde Oxidoreductases, Bacterial Proteins, Gene Deletion, Gene Expression, Gene Expression Regulation, Bacterial, Heme, Methyltransferases, Staphylococcus aureus
Show Abstract · Added March 15, 2018
is responsible for a significant amount of devastating disease. Its ability to colonize the host and cause infection is supported by a variety of proteins that are dependent on the cofactor heme. Heme is a porphyrin used broadly across kingdoms and is synthesized from common cellular precursors and iron. While heme is critical to bacterial physiology, it is also toxic in high concentrations, requiring that organisms encode regulatory processes to control heme homeostasis. In this work, we describe a posttranscriptional regulatory strategy in heme biosynthesis. The first committed enzyme in the heme biosynthetic pathway, glutamyl-tRNA reductase (GtrR), is regulated by heme abundance and the integral membrane protein HemX. GtrR abundance increases dramatically in response to heme deficiency, suggesting a mechanism by which responds to the need to increase heme synthesis. Additionally, HemX is required to maintain low levels of GtrR in heme-proficient cells, and inactivation of leads to increased heme synthesis. Excess heme synthesis in a Δ mutant activates the staphylococcal heme stress response, suggesting that regulation of heme synthesis is critical to reduce self-imposed heme toxicity. Analysis of diverse organisms indicates that HemX is widely conserved among heme-synthesizing bacteria, suggesting that HemX is a common factor involved in the regulation of GtrR abundance. Together, this work demonstrates that regulates heme synthesis by modulating GtrR abundance in response to heme deficiency and through the activity of the broadly conserved HemX. is a leading cause of skin and soft tissue infections, endocarditis, bacteremia, and osteomyelitis, making it a critical health care concern. Development of new antimicrobials against requires knowledge of the physiology that supports this organism's pathogenesis. One component of staphylococcal physiology that contributes to growth and virulence is heme. Heme is a widely utilized cofactor that enables diverse chemical reactions across many enzyme families. relies on many critical heme-dependent proteins and is sensitive to excess heme toxicity, suggesting must maintain proper intracellular heme homeostasis. Because provides heme for heme-dependent enzymes via synthesis from common precursors, we hypothesized that regulation of heme synthesis is one mechanism to maintain heme homeostasis. In this study, we identify that posttranscriptionally regulates heme synthesis by restraining abundance of the first heme biosynthetic enzyme, GtrR, via heme and the broadly conserved membrane protein HemX.
Copyright © 2018 Choby et al.
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8 MeSH Terms
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister F, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL, Housseau F
(2018) Cell Host Microbe 23: 203-214.e5
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Bacterial Toxins, Bacteroides fragilis, Carcinogenesis, Cell Line, Tumor, Colon, Colorectal Neoplasms, Enzyme Activation, Epithelial Cells, Female, Gene Deletion, HT29 Cells, Humans, Inflammation, Interleukin-17, Male, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Receptors, Interleukin-17, Receptors, Interleukin-8B, STAT3 Transcription Factor, Transcription Factor RelA
Show Abstract · Added March 20, 2018
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.
Copyright © 2018 Elsevier Inc. All rights reserved.
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26 MeSH Terms
Blocking TGF- and -Catenin Epithelial Crosstalk Exacerbates CKD.
Nlandu-Khodo S, Neelisetty S, Phillips M, Manolopoulou M, Bhave G, May L, Clark PE, Yang H, Fogo AB, Harris RC, Taketo MM, Lee E, Gewin LS
(2017) J Am Soc Nephrol 28: 3490-3503
MeSH Terms: Animals, Aristolochic Acids, Cell Nucleus, Collagen, Crosses, Genetic, Epithelium, Female, Gene Deletion, Kidney Failure, Chronic, Kidney Tubules, Proximal, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Transforming Growth Factor beta1, Wnt Proteins, beta Catenin
Show Abstract · Added July 18, 2017
The TGF- and Wnt/-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF- has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF- signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF- type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF- receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF- receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF- receptor impaired -catenin activity and Genetically restoring -catenin activity in proximal tubules lacking the TGF- receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF- receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of -catenin activity or an indirect effect of -catenin interacting with other growth factors. In conclusion, blocking TGF- and -catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.
Copyright © 2017 by the American Society of Nephrology.
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22 MeSH Terms
MybA, a transcription factor involved in conidiation and conidial viability of the human pathogen Aspergillus fumigatus.
Valsecchi I, Sarikaya-Bayram Ö, Wong Sak Hoi J, Muszkieta L, Gibbons J, Prevost MC, Mallet A, Krijnse-Locker J, Ibrahim-Granet O, Mouyna I, Carr P, Bromley M, Aimanianda V, Yu JH, Rokas A, Braus GH, Saveanu C, Bayram Ö, Latgé JP
(2017) Mol Microbiol 105: 880-900
MeSH Terms: Aspergillosis, Aspergillus fumigatus, Cell Wall, Fungal Proteins, Gene Deletion, Gene Expression Regulation, Fungal, Humans, Membrane Proteins, Sequence Deletion, Spores, Fungal, Transcription Factors, Virulence
Show Abstract · Added March 21, 2018
Aspergillus fumigatus, a ubiquitous human fungal pathogen, produces asexual spores (conidia), which are the main mode of propagation, survival and infection of this human pathogen. In this study, we present the molecular characterization of a novel regulator of conidiogenesis and conidial survival called MybA because the predicted protein contains a Myb DNA binding motif. Cellular localization of the MybA::Gfp fusion and immunoprecipitation of the MybA::Gfp or MybA::3xHa protein showed that MybA is localized to the nucleus. RNA sequencing data and a uidA reporter assay indicated that the MybA protein functions upstream of wetA, vosA and velB, the key regulators involved in conidial maturation. The deletion of mybA resulted in a very significant reduction in the number and viability of conidia. As a consequence, the ΔmybA strain has a reduced virulence in an experimental murine model of aspergillosis. RNA-sequencing and biochemical studies of the ΔmybA strain suggested that MybA protein controls the expression of enzymes involved in trehalose biosynthesis as well as other cell wall and membrane-associated proteins and ROS scavenging enzymes. In summary, MybA protein is a new key regulator of conidiogenesis and conidial maturation and survival, and plays a crucial role in propagation and virulence of A. fumigatus.
© 2017 John Wiley & Sons Ltd.
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12 MeSH Terms
Hepatic β-arrestin 2 is essential for maintaining euglycemia.
Zhu L, Rossi M, Cui Y, Lee RJ, Sakamoto W, Perry NA, Urs NM, Caron MG, Gurevich VV, Godlewski G, Kunos G, Chen M, Chen W, Wess J
(2017) J Clin Invest 127: 2941-2945
MeSH Terms: Animals, Blood Glucose, COS Cells, Cercopithecus aethiops, Diabetes Mellitus, Type 2, Diet, High-Fat, Gene Deletion, Gene Expression Regulation, Glucagon, Hepatocytes, Homeostasis, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Receptors, Glucagon, Signal Transduction, beta-Arrestin 1, beta-Arrestin 2
Show Abstract · Added March 14, 2018
An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein β-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific β-arrestin 2 deficiency did not affect hepatic insulin sensitivity or β-adrenergic signaling. Adult mice lacking β-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of β-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic β-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes.
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22 MeSH Terms
Structural and biochemical analyses reveal insights into covalent flavinylation of the Complex II homolog quinol:fumarate reductase.
Starbird CA, Maklashina E, Sharma P, Qualls-Histed S, Cecchini G, Iverson TM
(2017) J Biol Chem 292: 12921-12933
MeSH Terms: Amino Acid Substitution, Biocatalysis, Crystallography, X-Ray, Enzyme Stability, Escherichia coli, Escherichia coli Proteins, Flavin-Adenine Dinucleotide, Gene Deletion, Glutamic Acid, Hot Temperature, Models, Molecular, Molecular Docking Simulation, Mutagenesis, Site-Directed, Mutation, Oxidoreductases, Protein Conformation, Protein Denaturation, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Processing, Post-Translational, Protein Subunits, Recombinant Proteins, Structural Homology, Protein, Succinate Dehydrogenase
Show Abstract · Added April 1, 2019
The Complex II homolog quinol:fumarate reductase (QFR, FrdABCD) catalyzes the interconversion of fumarate and succinate at a covalently attached FAD within the FrdA subunit. The SdhE assembly factor enhances covalent flavinylation of Complex II homologs, but the mechanisms underlying the covalent attachment of FAD remain to be fully elucidated. Here, we explored the mechanisms of covalent flavinylation of the QFR FrdA subunit. Using a Δ strain, we show that the requirement for the assembly factor depends on the cellular redox environment. We next identified residues important for the covalent attachment and selected the FrdA residue, which contributes to proton shuttling during fumarate reduction, for detailed biophysical and structural characterization. We found that QFR complexes containing FrdA have a structure similar to that of the WT flavoprotein, but lack detectable substrate binding and turnover. In the context of the isolated FrdA subunit, the anticipated assembly intermediate during covalent flavinylation, FrdA variants had stability similar to that of WT FrdA, contained noncovalent FAD, and displayed a reduced capacity to interact with SdhE. However, small-angle X-ray scattering (SAXS) analysis of WT FrdA cross-linked to SdhE suggested that the FrdA residue is unlikely to contribute directly to the FrdA-SdhE protein-protein interface. We also found that no auxiliary factor is absolutely required for flavinylation, indicating that the covalent flavinylation is autocatalytic. We propose that multiple factors, including the SdhE assembly factor and bound dicarboxylates, stimulate covalent flavinylation by preorganizing the active site to stabilize the quinone-methide intermediate.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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Effects of deletion on body weight and cholesterol in mice.
Boortz KA, Syring KE, Pound LD, Mo H, Bastarache L, Oeser JK, McGuinness OP, Denny JC, O'Brien RM
(2017) J Mol Endocrinol 58: 127-139
MeSH Terms: Animals, Blood Glucose, Body Weight, Cholesterol, Diet, High-Fat, Fasting, Female, Gene Deletion, Gene Expression, Genetic Association Studies, Genetic Background, Glucose Tolerance Test, Glucose-6-Phosphatase, Insulin, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Pancreas, Polymorphism, Single Nucleotide
Show Abstract · Added March 14, 2018
Genome-wide association study (GWAS) data have linked the gene to variations in fasting blood glucose (FBG). encodes an islet-specific glucose-6-phosphatase catalytic subunit that forms a substrate cycle with the beta cell glucose sensor glucokinase. This cycle modulates the glucose sensitivity of insulin secretion and hence FBG. GWAS data have not linked to variations in body weight but we previously reported that female C57BL/6J -knockout (KO) mice were lighter than wild-type littermates on both a chow and high-fat diet. The purpose of this study was to compare the effects of deletion on FBG and body weight in both chow-fed and high-fat-fed mice on two other genetic backgrounds. FBG was reduced in KO mice largely independent of gender, genetic background or diet. In contrast, the effect of deletion on body weight was markedly influenced by these variables. Deletion of conferred a marked protection against diet-induced obesity in male mixed genetic background mice, whereas in 129SvEv mice deletion of had no effect on body weight. deletion also reduced plasma cholesterol levels in a manner dependent on gender, genetic background and diet. An association between and plasma cholesterol was also observed in humans through electronic health record-derived phenotype analyses. These observations suggest that the action of G6PC2 on FBG is largely independent of the influences of environment, modifier genes or epigenetic events, whereas the action of G6PC2 on body weight and cholesterol are influenced by unknown variables.
© 2017 Society for Endocrinology.
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21 MeSH Terms