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Results: 1 to 10 of 34

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Growth phase-dependent composition of the Helicobacter pylori exoproteome.
Snider CA, Voss BJ, McDonald WH, Cover TL
(2016) J Proteomics 130: 94-107
MeSH Terms: Bacterial Proteins, Cluster Analysis, Gastritis, Gene Expression Regulation, Bacterial, Helicobacter Infections, Helicobacter pylori, Humans, Mass Spectrometry, Protein Sorting Signals, Proteome, Proteomics, Solubility, Stomach
Show Abstract · Added October 8, 2015
Helicobacter pylori colonizes the human stomach and is associated with an increased risk of gastric cancer and peptic ulcer disease. Analysis of H. pylori protein secretion is complicated by the occurrence of bacterial autolysis. In this study, we analyzed the exoproteome of H. pylori at multiple phases of bacterial growth and identified 74 proteins that are selectively released into the extracellular space. These include proteins known to cause alterations in host cells, antigenic proteins, and additional proteins that have not yet been studied in any detail. The composition of the H. pylori exoproteome is dependent on the phase of bacterial growth. For example, the proportional abundance of the vacuolating toxin VacA in culture supernatant is higher during late growth phases than early growth phases, whereas the proportional abundance of many other proteins is higher during early growth phases. We detected marked variation in the subcellular localization of putative secreted proteins within soluble and membrane fractions derived from intact bacteria. By providing a comprehensive view of the H. pylori exoproteome, these results provide new insights into the array of secreted H. pylori proteins that may cause alterations in the gastric environment.
Published by Elsevier B.V.
0 Communities
2 Members
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13 MeSH Terms
Induction of lateral lumens through disruption of a monoleucine-based basolateral-sorting motif in betacellulin.
Singh B, Bogatcheva G, Starchenko A, Sinnaeve J, Lapierre LA, Williams JA, Goldenring JR, Coffey RJ
(2015) J Cell Sci 128: 3444-55
MeSH Terms: Amino Acid Sequence, Animals, Betacellulin, Cell Polarity, Dogs, EGF Family of Proteins, ErbB Receptors, Fluorescent Antibody Technique, Madin Darby Canine Kidney Cells, Mutation, Protein Sorting Signals, Protein Structure, Tertiary
Show Abstract · Added September 28, 2015
Directed delivery of EGF receptor (EGFR) ligands to the apical or basolateral surface is a crucial regulatory step in the initiation of EGFR signaling in polarized epithelial cells. Herein, we show that the EGFR ligand betacellulin (BTC) is preferentially sorted to the basolateral surface of polarized MDCK cells. By using sequential truncations and site-directed mutagenesis within the BTC cytoplasmic domain, combined with selective cell-surface biotinylation and immunofluorescence, we have uncovered a monoleucine-based basolateral-sorting motif (EExxxL, specifically (156)EEMETL(161)). Disruption of this sorting motif led to equivalent apical and basolateral localization of BTC. Unlike other EGFR ligands, BTC mistrafficking induced formation of lateral lumens in polarized MDCK cells, and this process was significantly attenuated by inhibition of EGFR. Additionally, expression of a cancer-associated somatic BTC mutation (E156K) led to BTC mistrafficking and induced lateral lumens in MDCK cells. Overexpression of BTC, especially mistrafficking forms, increased the growth of MDCK cells. These results uncover a unique role for BTC mistrafficking in promoting epithelial reorganization.
© 2015. Published by The Company of Biologists Ltd.
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4 Members
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12 MeSH Terms
Mitochondrial targeting of cytochrome P450 (CYP) 1B1 and its role in polycyclic aromatic hydrocarbon-induced mitochondrial dysfunction.
Bansal S, Leu AN, Gonzalez FJ, Guengerich FP, Chowdhury AR, Anandatheerthavarada HK, Avadhani NG
(2014) J Biol Chem 289: 9936-51
MeSH Terms: Adrenodoxin, Animals, Aryl Hydrocarbon Hydroxylases, Benzo(a)pyrene, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Cytochrome P-450 CYP1B1, Female, Humans, Male, Mice, Mice, Knockout, Mitochondria, Mutagenesis, Oxidation-Reduction, Oxygen Consumption, Polychlorinated Dibenzodioxins, Protein Sorting Signals, Protein Transport, Teratogens
Show Abstract · Added March 10, 2014
We report that polycyclic aromatic hydrocarbon (PAH)-inducible CYP1B1 is targeted to mitochondria by sequence-specific cleavage at the N terminus by a cytosolic Ser protease (polyserase 1) to activate the cryptic internal signal. Site-directed mutagenesis, COS-7 cell transfection, and in vitro import studies in isolated mitochondria showed that a positively charged domain at residues 41-48 of human CYP1B1 is part of the mitochondrial (mt) import signal. Ala scanning mutations showed that the Ser protease cleavage site resides between residues 37 and 41 of human CYP1B1. Benzo[a]pyrene (BaP) treatment induced oxidative stress, mitochondrial respiratory defects, and mtDNA damage that was attenuated by a CYP1B1-specific inhibitor, 2,3,4,5-tetramethoxystilbene. In support, the mitochondrial CYP1B1 supported by mitochondrial ferredoxin (adrenodoxin) and ferredoxin reductase showed high aryl hydrocarbon hydroxylase activity. Administration of benzo[a]pyrene or 2,3,7,8-tetrachlorodibenzodioxin induced similar mitochondrial functional abnormalities and oxidative stress in the lungs of wild-type mice and Cyp1a1/1a2-null mice, but the effects were markedly blunted in Cyp1b1-null mice. These results confirm a role for CYP1B1 in inducing PAH-mediated mitochondrial dysfunction. The role of mitochondrial CYP1B1 was assessed using A549 lung epithelial cells stably expressing shRNA against NADPH-cytochrome P450 oxidoreductase or mitochondrial adrenodoxin. Our results not only show conservation of the endoprotease cleavage mechanism for mitochondrial import of family 1 CYPs but also reveal a direct role for mitochondrial CYP1B1 in PAH-mediated oxidative and chemical damage to mitochondria.
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1 Members
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21 MeSH Terms
Tailoring of membrane proteins by alternative splicing of pre-mRNA.
Mittendorf KF, Deatherage CL, Ohi MD, Sanders CR
(2012) Biochemistry 51: 5541-56
MeSH Terms: Alternative Splicing, Alzheimer Disease, Animals, Humans, Introns, Membrane Proteins, Organ Specificity, Protein Folding, Protein Sorting Signals, Protein Transport, RNA Precursors, RNA, Messenger
Show Abstract · Added March 7, 2014
Alternative splicing (AS) of RNA is a key mechanism for diversification of the eukaryotic proteome. In this process, different mRNA transcripts can be produced through altered excision and/or inclusion of exons during processing of the pre-mRNA molecule. Since its discovery, AS has been shown to play roles in protein structure, function, and localization. Dysregulation of this process can result in disease phenotypes. Moreover, AS pathways are promising therapeutic targets for a number of diseases. Integral membrane proteins (MPs) represent a class of proteins that may be particularly amenable to regulation by alternative splicing because of the distinctive topological restraints associated with their folding, structure, trafficking, and function. Here, we review the impact of AS on MP form and function and the roles of AS in MP-related disorders such as Alzheimer's disease.
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2 Members
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12 MeSH Terms
Cell-permeable NM23 blocks the maintenance and progression of established pulmonary metastasis.
Lim J, Jang G, Kang S, Lee G, Nga do TT, Phuong do TL, Kim H, El-Rifai W, Ruley HE, Jo D
(2011) Cancer Res 71: 7216-25
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Tumor, Cell Movement, Cell-Penetrating Peptides, Disease Progression, Female, HCT116 Cells, Humans, Lung Neoplasms, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinase Kinases, Molecular Sequence Data, Molecular Targeted Therapy, NIH 3T3 Cells, NM23 Nucleoside Diphosphate Kinases, Neoplasm Metastasis, Protein Sorting Signals, Recombinant Fusion Proteins, Xenograft Model Antitumor Assays
Show Abstract · Added March 10, 2014
Occult metastases are a major cause of cancer mortality, even among patients undergoing curative resection. Therefore, practical strategies to target the growth and persistence of already established metastases would provide an important advance in cancer treatment. Here, we assessed the potential of protein therapy using a cell permeable NM23-H1 metastasis suppressor protein. Hydrophobic transduction domains developed from a screen of 1,500 signaling peptide sequences enhanced the uptake of the NM23 protein by cultured cells and systemic delivery to animal tissues. The cell-permeable (CP)-NM23 inhibited metastasis-associated phenotypes in tumor cell lines, blocked the establishment of lung metastases, and cleared already established pulmonary metastases, significantly prolonging the survival of tumor-bearing animals. Therefore, these results establish the potential use of cell-permeable metastasis suppressors as adjuvant therapy against disseminated cancers.
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2 Members
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21 MeSH Terms
Discovery of an operon that participates in agmatine metabolism and regulates biofilm formation in Pseudomonas aeruginosa.
Williams BJ, Du RH, Calcutt MW, Abdolrasulnia R, Christman BW, Blackwell TS
(2010) Mol Microbiol 76: 104-19
MeSH Terms: Agmatine, Base Sequence, Biofilms, Cell Fractionation, Gene Expression Profiling, Gene Order, Hydrolases, Metabolic Networks and Pathways, Models, Biological, Molecular Sequence Data, Mutagenesis, Site-Directed, Operon, Periplasm, Promoter Regions, Genetic, Protein Sorting Signals, Protein Transport, Pseudomonas aeruginosa
Show Abstract · Added February 19, 2015
Agmatine is the decarboxylation product of arginine and a number of bacteria have devoted enzymatic pathways for its metabolism. Pseudomonas aeruginosa harbours the aguBA operon that metabolizes agmatine to putrescine, which can be subsequently converted into other polyamines or shunted into the TCA cycle for energy production. We discovered an alternate agmatine operon in the P. aeruginosa strain PA14 named agu2ABCA' that contains two genes for agmatine deiminases (agu2A and agu2A'). This operon was found to be present in 25% of clinical P. aeruginosa isolates. Agu2A' contains a twin-arginine translocation signal at its N-terminus and site-directed mutagenesis and cell fractionation experiments confirmed this protein is secreted to the periplasm. Analysis of the agu2ABCA' promoter demonstrates that agmatine induces expression of the operon during the stationary phase of growth and during biofilm growth and agu2ABCA' provides only weak complementation of aguBA, which is induced during log phase. Biofilm assays of mutants of all three agmatine deiminase genes in PA14 revealed that deletion of agu2ABCA', specifically its secreted product Agu2A', reduces biofilm production of PA14 following addition of exogenous agmatine. Together, these findings reveal a novel role for the agu2ABCA' operon in the biofilm development of P. aeruginosa.
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17 MeSH Terms
Identification of genetic variants of human cytochrome P450 2D6 with impaired mitochondrial targeting.
Sangar MC, Anandatheerthavarada HK, Martin MV, Guengerich FP, Avadhani NG
(2010) Mol Genet Metab 99: 90-7
MeSH Terms: Alternative Splicing, Amino Acid Sequence, Animals, Cytochrome P-450 CYP2D6, Exons, Genetic Variation, Humans, Liver, Microsomes, Mitochondria, Liver, Mitochondrial Proteins, Molecular Sequence Data, Mutation, Protein Sorting Signals, Protein Transport, Rats, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added March 26, 2014
Human cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of approximately 20% of drugs in common clinical use. The CYP2D6 gene locus is highly polymorphic. Many of the polymorphisms have been shown to be clinically relevant and can account for inter-individual differences in the metabolism of specific drugs. In addition to the established sources of variability in CYP2D6-dependent drug metabolism, a recent study in our laboratory identified CYP2D6 in the mitochondria of human liver samples and found that it is metabolically active in this novel location. In the present study we show that mutations are present in the targeting signal region of CYP2D6 that may help to account for the inter-individual variability that was observed previously in the level of the mitochondrial enzyme in human liver samples. These mutations were identified within the ER targeting domain, the proline-rich domain as well as the putative protein kinase A (PKA) and protein kinase C (PKC)-specific phosphorylation sites. In vitro studies demonstrate that the mutations identified in the targeting signals affect the efficiency of mitochondrial targeting of CYP2D6. Since the mitochondrial enzyme has been shown to be active in drug metabolism, this pharmacogenetic variation could play a role in modulating the response of an individual to drug therapy.
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1 Members
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17 MeSH Terms
Human liver mitochondrial cytochrome P450 2D6--individual variations and implications in drug metabolism.
Sangar MC, Anandatheerthavarada HK, Tang W, Prabu SK, Martin MV, Dostalek M, Guengerich FP, Avadhani NG
(2009) FEBS J 276: 3440-53
MeSH Terms: Amino Acid Sequence, Animals, COS Cells, Chlorocebus aethiops, Coumarins, Cyclic AMP-Dependent Protein Kinases, Cytochrome P-450 CYP2D6, Ethanolamines, Humans, Isoenzymes, Microsomes, Liver, Molecular Sequence Data, Pharmaceutical Preparations, Protein Sorting Signals
Show Abstract · Added March 26, 2014
Constitutively expressed human cytochrome P450 2D6 (CYP2D6; EC 1.14.14.1) is responsible for the metabolism of approximately 25% of drugs in common clinical use. It is widely accepted that CYP2D6 is localized in the endoplasmic reticulum of cells; however, we have identified this enzyme in the mitochondria of human liver samples and found that extensive inter-individual variability exists with respect to the level of the mitochondrial enzyme. Metabolic assays using 7-methoxy-4-aminomethylcoumarin as a substrate show that the human liver mitochondrial enzyme is capable of oxidizing this substrate and that the catalytic activity is supported by mitochondrial electron transfer proteins. In the present study, we show that CYP2D6 contains an N-terminal chimeric signal that mediates its bimodal targeting to the endoplasmic reticulum and mitochondria. In vitro mitochondrial import studies using both N-terminal deletions and point mutations suggest that the mitochondrial targeting signal is localized between residues 23-33 and that the positively-charged residues at positions 24, 25, 26, 28 and 32 are required for mitochondrial targeting. The importance of the positively-charged residues was confirmed by transient transfection of a CYP2D6 mitochondrial targeting signal mutant in COS-7 cells. Both the mitochondria and the microsomes from a CYP2D6 stable expression cell line contain the enzyme and both fractions exhibit bufuralol 1'-hydroxylation activity, which is completely inhibited by CYP2D6 inhibitory antibody. Overall, these results suggest that the targeting of CYP2D6 to mitochondria could be an important physiological process that has significance in xenobiotic metabolism.
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1 Members
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14 MeSH Terms
Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides.
Gomez JA, Gama V, Yoshida T, Sun W, Hayes P, Leskov K, Boothman D, Matsuyama S
(2007) Biochem Soc Trans 35: 797-801
MeSH Terms: Animals, Antigens, Nuclear, DNA-Binding Proteins, Drug Delivery Systems, Humans, Ku Autoantigen, Oligopeptides, Protein Sorting Signals, Protein Transport, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
We found that Ku70, a known DNA repair factor, has a novel function to bind and inhibit Bax (Bcl-2-associated X protein), a key mediator of apoptosis. Pentapeptides derived from the Bax-binding domain of Ku70 were cell-permeable and protected cells from Bax-mediated apoptosis. These pentapeptides were called BIPs (Bax-inhibiting peptides). BIPs may become a useful therapeutic tool to reduce cellular damage. We also generated BIP mutant pentapeptides that do not inhibit Bax, but retain their cell-penetrating activity. Since both BIPs and BIP mutants are cell-permeable, these peptides were designated CPP5s (cell-penetrating pentapeptides). Among the CPP5s discovered, VPTLK (BIP) and KLPVM (BIP mutant) were confirmed to possess protein transduction activity by examination of the delivery of GFP (green fluorescent protein) into cells by these peptides. The mechanism of cell penetration by CPP5s is not known. CPP5s enter the cell at 0 and 4 degrees C. In preliminary studies, various inhibitors of endocytosis and pinocytosis did not show any significant suppression of CPP5 cell entry. CPP5s have very low toxicity in vitro and in vivo and so may be useful tools in order to develop non-toxic drug-delivery technologies.
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10 MeSH Terms
Functional characterization of chimpanzee cytomegalovirus chemokine, vCXCL-1(CCMV).
Miller-Kittrell M, Sai J, Penfold M, Richmond A, Sparer TE
(2007) Virology 364: 454-65
MeSH Terms: Amino Acid Sequence, Animals, Apoptosis, Baculoviridae, CD11b Antigen, CD11c Antigen, Calcium Signaling, Chemokines, CXC, Conserved Sequence, Cytomegalovirus, Humans, In Vitro Techniques, Molecular Sequence Data, Neutrophils, Pan troglodytes, Protein Sorting Signals, Receptors, Interleukin-8B, Sequence Homology, Amino Acid, Viral Proteins, Virulence
Show Abstract · Added May 31, 2013
Human cytomegaloviruses (HCMVs) are important pathogens in immunocompromised patients and newborns. The viral chemokine, vCXCL-1, of the Toledo (Tol) strain of HCMV has been implicated in HCMV virulence. Chimpanzee CMV (CCMV) has several genes with similarity to the vCXCL-1(Tol) gene, UL146. In order to test whether the CCMV viral chemokine, vCXCL-1(CCMV), is similar to vCXCL-1(Tol), we characterized its function in vitro. Receptor binding, activation, chemotaxis, signaling, and apoptosis in neutrophils were compared between vCXCL-1(Tol) and vCXCL-1(CCMV) and host chemokines. Although the homologues had similar activation potentials, chemotactic properties, and signaling, vCXCL-1(CCMV) had a approximately 70-fold lower affinity for CXCR2 and displayed differences in integrin upregulation and neutrophil apoptosis. These data demonstrate that in spite of extensive amino acid variability in vCXCL-1, CCMV may provide a model for assessing the role of vCXCL-1 in CMV pathogenesis in vivo.
2 Communities
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20 MeSH Terms