Copper-Induced Stimulation of Extracellular Signal-Regulated Kinase in Trout Hepatocytes: The Role of Reactive Oxygen Species, Ca2+, and Cell Energetics and the Impact of Extracellular Signal-Regulated Kinase Signaling on Apoptosis and Necrosis
Identifieur interne : 001D54 ( Main/Exploration ); précédent : 001D53; suivant : 001D55Copper-Induced Stimulation of Extracellular Signal-Regulated Kinase in Trout Hepatocytes: The Role of Reactive Oxygen Species, Ca2+, and Cell Energetics and the Impact of Extracellular Signal-Regulated Kinase Signaling on Apoptosis and Necrosis
Auteurs : Muhammad Nawaz [Autriche] ; Claudia Manzl [Autriche] ; Veronika Lacher ; Gerhard Krumschnabel [Autriche]Source :
- Toxicological Sciences [ 1096-6080 ] ; 2006.
Abstract
The present study investigated if copper (Cu) exposure of trout hepatocytes, which stimulates formation of reactive oxygen species (ROS) and increases intracellular free Ca2+ (Ca2+i), leads to an activation of extracellular signal-regulated kinase (ERK), the mechanisms underlying this activation, and the role of ERK signaling in cell death. Cu stimulated a time- and dose-dependent increase of phosphorylated extracellular signal-regulated kinase (pERK), and preventing the associated Ca2+ influx or radical formation diminished or inhibited ERK activation, respectively. Furthermore, Cu enhanced caspase 3/7 activity and necrosis, and both effects were inhibited by treatments diminishing radical production and by chelating extracellular Ca2+. In addition, ERK activity, and to a lesser extent caspase activity, was reduced by inhibiting mitochondrial ATP production, suggesting ATP dependence of the process. Inhibition of the ERK activator MEK, as well as of p38, significantly reduced caspase activation and necrosis, whereas c-Jun N-terminal kinase (JNK) inhibition diminished only caspase activity. Likewise, inhibition of MEK and p38, but not of JNK, prevented Cu-induced ROS production. In summary, we found that stimulation of ERK by Cu exposure of trout hepatocytes is dependent on radical formation and ATP, whereas Ca2+ only modulates ERK activity. At the same time, activated ERK, as well as p38, contributes to enhanced ROS formation, whereas JNK did not. All three mitogen-activated protein kinases appear to promote apoptotic cell death upon Cu exposure, and ERK and p38 also stimulate necrosis.
Url:
DOI: 10.1093/toxsci/kfl006
Affiliations:
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Copper-Induced Stimulation of Extracellular Signal-Regulated Kinase in Trout Hepatocytes: The Role of Reactive Oxygen Species, Ca2+, and Cell Energetics and the Impact of Extracellular Signal-Regulated Kinase Signaling on Apoptosis and Necrosis</title><author><name sortKey="Nawaz, Muhammad" sort="Nawaz, Muhammad" uniqKey="Nawaz M" first="Muhammad" last="Nawaz">Muhammad Nawaz</name></author><author><name sortKey="Manzl, Claudia" sort="Manzl, Claudia" uniqKey="Manzl C" first="Claudia" last="Manzl">Claudia Manzl</name></author><author><name sortKey="Lacher, Veronika" sort="Lacher, Veronika" uniqKey="Lacher V" first="Veronika" last="Lacher">Veronika Lacher</name></author><author><name sortKey="Krumschnabel, Gerhard" sort="Krumschnabel, Gerhard" uniqKey="Krumschnabel G" first="Gerhard" last="Krumschnabel">Gerhard Krumschnabel</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:4E2242737D6B4A59BBCEFA29E84FC1C7BB7921BB</idno><date when="2006" year="2006">2006</date><idno type="doi">10.1093/toxsci/kfl006</idno><idno type="url">https://api.istex.fr/ark:/67375/HXZ-9RQ58G8M-K/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">002884</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">002884</idno><idno type="wicri:Area/Istex/Curation">002884</idno><idno type="wicri:Area/Istex/Checkpoint">000C22</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000C22</idno><idno type="wicri:doubleKey">1096-6080:2006:Nawaz M:copper:induced:stimulation</idno><idno type="wicri:Area/Main/Merge">001D66</idno><idno type="wicri:Area/Main/Curation">001D54</idno><idno type="wicri:Area/Main/Exploration">001D54</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Copper-Induced Stimulation of Extracellular Signal-Regulated Kinase in Trout Hepatocytes: The Role of Reactive Oxygen Species, Ca<hi rend="superscript">2+</hi>, and Cell Energetics and the Impact of Extracellular Signal-Regulated Kinase Signaling on Apoptosis and Necrosis</title><author><name sortKey="Nawaz, Muhammad" sort="Nawaz, Muhammad" uniqKey="Nawaz M" first="Muhammad" last="Nawaz">Muhammad Nawaz</name><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr" wicri:curation="lc">Autriche</country><wicri:regionArea>Center of Molecular Biosciences, Leopold Franzens Universität Innsbruck, A-6020 Innsbruck</wicri:regionArea><wicri:noRegion>A-6020 Innsbruck</wicri:noRegion></affiliation></author><author><name sortKey="Manzl, Claudia" sort="Manzl, Claudia" uniqKey="Manzl C" first="Claudia" last="Manzl">Claudia Manzl</name><affiliation wicri:level="1"><country xml:lang="fr">Autriche</country><wicri:regionArea>Laboratory of Comparative Immunology, Division of Experimental Pathophysiology and Immunology, Innsbruck Medical University, A-6020 Innsbruck</wicri:regionArea><wicri:noRegion>A-6020 Innsbruck</wicri:noRegion></affiliation></author><author><name sortKey="Lacher, Veronika" sort="Lacher, Veronika" uniqKey="Lacher V" first="Veronika" last="Lacher">Veronika Lacher</name><affiliation><wicri:noCountry code="no comma">Institut für Zoologie und Limnologie and</wicri:noCountry></affiliation></author><author><name sortKey="Krumschnabel, Gerhard" sort="Krumschnabel, Gerhard" uniqKey="Krumschnabel G" first="Gerhard" last="Krumschnabel">Gerhard Krumschnabel</name><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr" wicri:curation="lc">Autriche</country><wicri:regionArea>Center of Molecular Biosciences, Leopold Franzens Universität Innsbruck, A-6020 Innsbruck</wicri:regionArea><wicri:noRegion>A-6020 Innsbruck</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Autriche</country><wicri:regionArea>To whom correspondence should be addressed at Institut für Zoologie und Limnologie, Leopold Franzens Universität Innsbruck, Technikerstraße 25, A-6020 Innsbruck</wicri:regionArea><wicri:noRegion>A-6020 Innsbruck</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Toxicological Sciences</title><title level="j" type="abbrev">Toxicol. Sci.</title><idno type="ISSN">1096-6080</idno><idno type="eISSN">1096-0929</idno><imprint><publisher>Oxford University Press</publisher><date type="e-published" when="2006-05-03">2006</date><date when="2006-08">2006</date><biblScope unit="vol">92</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="464">464</biblScope><biblScope unit="page" to="475">475</biblScope></imprint><idno type="ISSN">1096-6080</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1096-6080</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The present study investigated if copper (Cu) exposure of trout hepatocytes, which stimulates formation of reactive oxygen species (ROS) and increases intracellular free Ca2+ (Ca2+i), leads to an activation of extracellular signal-regulated kinase (ERK), the mechanisms underlying this activation, and the role of ERK signaling in cell death. Cu stimulated a time- and dose-dependent increase of phosphorylated extracellular signal-regulated kinase (pERK), and preventing the associated Ca2+ influx or radical formation diminished or inhibited ERK activation, respectively. Furthermore, Cu enhanced caspase 3/7 activity and necrosis, and both effects were inhibited by treatments diminishing radical production and by chelating extracellular Ca2+. In addition, ERK activity, and to a lesser extent caspase activity, was reduced by inhibiting mitochondrial ATP production, suggesting ATP dependence of the process. Inhibition of the ERK activator MEK, as well as of p38, significantly reduced caspase activation and necrosis, whereas c-Jun N-terminal kinase (JNK) inhibition diminished only caspase activity. Likewise, inhibition of MEK and p38, but not of JNK, prevented Cu-induced ROS production. In summary, we found that stimulation of ERK by Cu exposure of trout hepatocytes is dependent on radical formation and ATP, whereas Ca2+ only modulates ERK activity. At the same time, activated ERK, as well as p38, contributes to enhanced ROS formation, whereas JNK did not. All three mitogen-activated protein kinases appear to promote apoptotic cell death upon Cu exposure, and ERK and p38 also stimulate necrosis.</div></front></TEI><affiliations><list><country><li>Autriche</li></country></list><tree><noCountry><name sortKey="Lacher, Veronika" sort="Lacher, Veronika" uniqKey="Lacher V" first="Veronika" last="Lacher">Veronika Lacher</name></noCountry><country name="Autriche"><noRegion><name sortKey="Nawaz, Muhammad" sort="Nawaz, Muhammad" uniqKey="Nawaz M" first="Muhammad" last="Nawaz">Muhammad Nawaz</name></noRegion><name sortKey="Krumschnabel, Gerhard" sort="Krumschnabel, Gerhard" uniqKey="Krumschnabel G" first="Gerhard" last="Krumschnabel">Gerhard Krumschnabel</name><name sortKey="Krumschnabel, Gerhard" sort="Krumschnabel, Gerhard" uniqKey="Krumschnabel G" first="Gerhard" last="Krumschnabel">Gerhard Krumschnabel</name><name sortKey="Manzl, Claudia" sort="Manzl, Claudia" uniqKey="Manzl C" first="Claudia" last="Manzl">Claudia Manzl</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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