Biofactors - Volume 17, issue 1-4

Authors: Forman, Henry Jay | Dickinson, Dale A.

Article Type: Research Article

Keywords: glutamate cysteine ligase, thioredoxin, hydrogen peroxide, 4-hydroxynonenal, GCL, GCS

Citation: BioFactors, vol. 17, no. 1-4, pp. 1-12, 2003

Authors: Rojas, E. | Shi, Z.-Z. | Valverde, M. | Paules, R.S. | Habib, G.M. | Lieberman, M.W.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 13-19, 2003

Authors: Mandl, Jôzsef | Bánhegyi, Gábor

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 21-26, 2003

Authors: Csala, Miklós | Fulceri, Rosella | Mandl, József | Benedetti, Angelo | Bánhegyi, Gábor

Article Type: Research Article

Abstract: Glutathione transport through the endo/sarcoplasmic reticulum (ER/SR) membrane might play a role in the maintenance of the thiol redox potential difference between the lumen and the cytosol. The transport of glutathione (both GSH and glutathione disulfide, GSSG) is entirely different in the ER and SR membranes. The transport measurements based on either rapid filtration or light scattering techniques revealed that the SR membrane transports glutathione much faster than the hepatic ER membrane or microsomal …membranes prepared from heart or brain. The fastest transport has been measured in the membrane of muscle terminal cisternae, which is enriched in ryanodine receptor type 1 (RyR1). All the studied membranes have been found to be equally impermeable to various hydrophilic substances of similar size to glutathione, thus the glutathione transport in muscle microsomes and terminal cysternae as well as the correlation between the rate of glutathione transport and the abundance of RyR1 are specific. In both muscle microsomes and terminal cysternae, glutathione influx can be either inhibited or activated by antagonists and agonists of the ryanodine receptor, respectively, while these agents do not influence the transport of other small permeant molecules. These findings strongly suggest that the ryanodine receptor channel activity is directly associated with glutathione transport activity in the skeletal muscle sarcoplasmic reticulum membrane. Show more

Citation: BioFactors, vol. 17, no. 1-4, pp. 27-35, 2003

Authors: Bánhegyi, Gábor | Csala, Miklós | Szarka, András | Varsányi, Marianne | Benedetti, Angelo | Mandl, József

Article Type: Research Article

Abstract: Both in prokaryotic and eukaryotic cells, disulfide bond formation (oxidation and isomerization steps) are catalyzed exclusively in extracytoplasmic compartments. In eukaryotes, protein folding and disulfide bond formation are coupled processes that occur both co- and posttranslationally in the endoplasmic reticulum (ER), which is the main site of the synthesis and posttranslational modification of secretory and membrane proteins. The formation of a disulfide bond from the thiol groups of two cysteine residues requires …the removal of two electrons, consequently, these bonds cannot form spontaneously; an oxidant is needed to accept the electrons. In aerobic conditions the ultimate electron acceptor is usually oxygen; however, oxygen itself is not effective in protein thiol oxidation. Therefore, a small molecular weight membrane permeable compound should be supposed for the transfer of electrons from the ER lumen. The aim of the present study was the investigation of the role of ascorbate/dehydroascorbate redox couple in oxidative folding of proteins. We demonstrated that ascorbate addition or its in situ synthesis from gulonolactone results in protein thiol (and/or glutathione; GSH) oxidation in rat liver microsomes. Since microsomal membrane is hardly permeable to ascorbate, the existence of a transport metabolon was hypothesized. Three components of the system have been described and partially characterized: (i) A microsomal metalloenzyme is responsible for ascorbate oxidation on the outer surface of the ER. Ascorbate oxidation results in ascorbate free radical and dehydroascorbate production. (ii) Facilitated diffusion of dehydroascorbate is present in microsomal vesicles. The transport is presumably mediated by a GLUT-type transporter. On the contrary, the previously hypothesized glutathione disulfide (GSSG) transport is practically absent, while GSH is transported with a moderate velocity. (iii) Protein disulfide isomerase catalyzes the reduction of dehydroascorbate in the ER lumen. Both GSH and protein thiols can be electron donors in the process. Intraluminal dehydroascorbate reduction and the consequent ascorbate accumulation strictly correlate with protein disulfide isomerase activity and protein thiol concentration. The concerted action of the three components of the system results in the intraluminal accumulation of ascorbate, protein disulfide and GSSG. In fact, intraluminal ascorbate and GSSG accumulation could be observed upon dehydroascorbate and GSH uptake. In conclusion, ascorbate is able to promote protein disulfide formation in an in vitro system. Further work is needed to justify its role in intact cellular and in vivo systems, as well as to explore the participation of other antioxidants (e.g. tocopherol, ubiquinone, and vitamin K) in the electron transfer chain responsible for oxidative protein folding in the ER. Show more

Citation: BioFactors, vol. 17, no. 1-4, pp. 37-46, 2003

Authors: Nöhammer, Gerhard

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 47-60, 2003

Authors: Wojtczak, Lech | Slyshenkov, Vyacheslav S.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 61-73, 2003

Authors: Balcerczyk, A. | Grzelak, A. | Janaszewska, A. | Jakubowski, W. | Koziol, S. | Marszalek, M. | Rychlik, B. | Soszynski, M. | Bilinski, T. | Bartosz, G.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 75-82, 2003

Authors: Budde, Heike | Flohé, Leopold

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 83-92, 2003

Authors: Brigelius-Flohé, Regina | Flohé, Leopold

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 93-102, 2003

Authors: Homolya, | Váradi, András | Sarkadi, Balázs

Article Type: Research Article

Abstract: Many endogenous or xenobiotic lipophilic substances are eliminated from the cells by the sequence of oxidation, conjugation to an anionic group (glutathione, glucuronate or sulfate) and transport across the plasma membrane into the extracellular space. The latter step is mediated by integral membrane glycoproteins belonging to the superfamily of ATP-Binding Cassette (ABC) transporters. A subfamily, referred as ABCC, includes the famous/infamous cystic fibrosis transmembrane regulator (CFTR), the sulfonylurea receptors (SUR 1 and …2), and the multidrug resistance-associated proteins (MRPs). The name of the MRPs refers to their potential role in clinical multidrug resistance, a phenomenon that hinders the effective chemotherapy of tumors. The MRPs that have been functionally characterized so far share the property of ATP-dependent export pumps for conjugates with glutathione (GSH), glucuronate or sulfate. MRP1 and MRP2 are also mediating the cotransport of unconjugated amphiphilic compounds together with free GSH. MRP3 preferentially transports glucuronides but not glutathione S-conjugates or free GSH. MRP1 and MRP2 also contribute to the control of the intracellular glutathione disulfide (GSSG) level. Although these proteins are low affinity GSSG transporters, they can play essential role in response to oxidative stress when the activity of GSSG reductase becomes rate limiting. The human MRP4, MRP5 and MRP6 have only partially been characterized. However, it has been revealed that MRP4 can function as an efflux pump for cyclic nucleotides and nucleoside analogues, used as anti-HIV drugs. MRP5 also transports GSH conjugates, nucleoside analogues, and possibly heavy metal complexes. Transport of glutathione S-conjugates mediated by MRP6, the mutation of which causes pseudoxantoma elasticum, has recently been shown. In summary, numerous members of the multidrug resistance-associated protein family serve as export pumps that prevent the accumulation of anionic conjugates and GSSG in the cytoplasm, and play, therefore, an essential role in detoxification and defense against oxidative stress. Show more

Citation: BioFactors, vol. 17, no. 1-4, pp. 103-114, 2003

Authors: Coles, Brian F. | Kadlubar, Fred F.

Article Type: Research Article

Abstract: The glutathione S-transferases (GSTs) catalyze the GSH-dependent detoxification of reactive electrophiles such as genotoxic chemical carcinogens and cytotoxic chemotherapeutic agents. Allelic polymorphism in the GSTs has been used to investigate the hypothesis that GSTs are involved in susceptibility to human cancers. Such studies have resulted in low penetrance, high prevalence associations between cancer risk and GST polymorphisms. By examination of interindividual variation of GST expression it becomes clear that GST genotype alone …is not an accurate predictor of GST expression. GST expression is tissue specific and interindividual variation of expression is at least 7-fold in normal tissues. Thus, populations of the same genotype are actually heterogeneous as regards expression. Similarly, polymorphisms are not effective in all tissues and GST induction is not independent of genotype. Mechanistic models for chemical aspects of colorectal cancer and chemotherapy for breast cancer demonstrate some of the ways by which such interactions can be studied and the potential for future studies. Show more

Citation: BioFactors, vol. 17, no. 1-4, pp. 115-130, 2003

Authors: Duvoix, A. | Schmitz, M. | Schnekenburger, M. | Dicato, M. | Morceau, F. | Galteau, M.-M. | Diederich, M.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 131-138, 2003

Authors: Stark, Avishay-Abraham | Porat, Noga | Volohonsky, Gloria | Komlosh, Arthur | Bluvshtein, Evgenia | Tubi, Chen | Steinberg, Pablo

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 139-149, 2003

Authors: Huseby, N.-E. | Asare, N. | Wetting, S. | Mikkelsen, I.M. | Mortensen, B. | Wellman, M.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 151-160, 2003

Authors: Jean, Jyh-Chang | Liu, Yue | Joyce-Brady, Martin

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 161-173, 2003

Authors: Enoiu, Milica | Herber, Régine | Leroy, Pierre | Wellman, Maria

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 175-185, 2003

Authors: Dominici, Silvia | Paolicchi, Aldo | Lorenzini, Evelina | Maellaro, Emilia | Comporti, Mario | Pieri, Lisa | Minotti, Giorgio | Pompella, Alfonso

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 187-198, 2003

Authors: Emdin, Michele | Passino, Claudio | Pompella, Alfonso | Paolicchi, Aldo

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 199-205, 2003

Authors: Bast, Aalt | Haenen, Guido R.M.M.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 207-213, 2003

Authors: Barber, Vicki S. | Griffiths, Helen R.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 215-228, 2003

Authors: Biesalski, Hans Konrad | Frank, Jürgen

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 229-240, 2003

Authors: Matthias, Lisa J. | Yam, Patricia T.W. | Jiang, Xing-Mai | Hogg, Philip J.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 241-248, 2003

Authors: Papp, Eszter | Nardai, Gábor | Sőti, Csaba | Csermely, Péter

Article Type: Research Article

Abstract: Protection against oxidative stress is highly interrelated with the function of the most ancient cellular defense system, the network of molecular chaperones, heat shock, or stress-proteins. These ubiquitous, conserved proteins help other proteins and macromolecules to fold or re-fold and reach their final, native conformation. Redox regulation of protein folding becomes especially important during the preparation of extracellular proteins to the outside oxidative milieu, which should take place in a gradual and step-by-step …controlled manner in the endoplasmic reticulum or in the periplasm. Several chaperones, such as members of the Hsp33 family in yeast and the plethora of small heat shock proteins as well as one of the major chaperones, Hsp70 are able to act against cytoplasmic oxidative damage. Abrupt changes of cellular redox status lead to chaperone induction. The function of several chaperones is tightly regulated by the surrounding redox conditions. Moreover, our recent data suggest that chaperones may act as a central switchboard for the transmission of redox changes in the life of the cell. Show more

Citation: BioFactors, vol. 17, no. 1-4, pp. 249-257, 2003

Authors: Nardai, Gábor | Korcsmáros, Tamás | Papp, Eszter | Csermely, Péter

Article Type: Research Article

Abstract: The endoplasmic reticulum (ER), similary to other subcompartments of the eukaryotic cell possesses a relatively oxidizing environment. The special milieu of ER lumen is important for many ER-specific processes (redox protein folding, glycoprotein synthesis, quality control of secreted proteins, antigen presentation, etc.). Despite of the vital importance of redox regulation in the ER, we have a surprisingly fragmented knowledge about the mechanisms responsible for the ER redox balance. Moreover, new observations on disulfide …bridge synthesis and on glutathione functions urge us to revise our recent theories based on many indirect and in vitro results. We have also very little information about the effects of different pathological conditions on the thiol metabolism and redox folding in the ER. Examining the role of molecular chaperones in the cellular pathology of diabetes mellitus we found that the ER redox environment shifted to a more reducing state, which was followed by changes of the thiol metabolism and structural-functional changes of the protein machinery involved in the redox folding process in diabetes. The possible consequences of these unexpected changes are also discussed. Show more

Citation: BioFactors, vol. 17, no. 1-4, pp. 259-267, 2003

Authors: Cotgreave, Ian A.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 269-277, 2003

Authors: Mura, U. | Cappiello, M. | Vilardo, P.G. | Cecconi, I. | Dal Monte, M. | Del Corso, A.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 279-285, 2003

Authors: Torres, Martine | Forman, Henry Jay

Article Type: Research Article

Abstract: The mitogen-activated protein (MAP) kinases are a large family of proline-directed, serine/threonine kinases that require tyrosine and threonine phosphorylation of a TxY motif in the activation loop for activation through a phosphorylation cascade involving a MAPKKK, MAPKK and MAPK, often referred to as the MAP kinase module. Three separate such modules have been identified, based on the TxY motif of the MAP kinase and the dual-specificity kinases that strictly phosphorylate their specific TxY sequence. They are …the extracellular signal regulated kinases (ERKs), c-jun N-terminal kinases (JNKs) and p38 MAPKs. The ERKs are mainly associated with proliferation and differentiation while the JNKs and p38MAP kinases regulate responses to cellular stresses. Redox homeostasis is critical for proper cellular function. While reactive oxygen species (ROS) and oxidative stress have been implicated in injury, a rapidly growing literature suggests that a transient increase in ROS levels is an important mediator of proliferation and results in activation of various signaling molecules and pathways, among which the MAP kinases. This review will summarize the role of ROS in MAP kinase activation in various systems, including in macrophages, cells of myeloid origin that play an essential role in inflammation and express a multi-component NADPH oxidase that catalyzes the receptor-regulated production of ROS. Show more

Keywords: MAP kinase, signal transduction, redox signaling, thiols

Citation: BioFactors, vol. 17, no. 1-4, pp. 287-296, 2003

Authors: Tirosh, Oren | Shilo, Shani | Aronis, Anna | Sen, Chandan K.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 297-306, 2003

Authors: Watson, Walter H. | Chen, Yan | Jones, Dean P.

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 307-314, 2003

Authors: Lunec, Joseph | Holloway, K. | Cooke, Marcus | Evans, Mark

Article Type: Research Article

Citation: BioFactors, vol. 17, no. 1-4, pp. 315-324, 2003