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Research ArticleArticle

4-Hydroxy-2-nonenal Adduction of Extracellular Signal-Regulated Kinase (Erk) and the Inhibition of Hepatocyte Erk-Est–Like Protein-1-Activating Protein-1 Signal Transduction

Brante P. Sampey, David L. Carbone, Jonathan A. Doorn, Derek A. Drechsel and Dennis R. Petersen
Molecular Pharmacology March 2007, 71 (3) 871-883; DOI: https://doi.org/10.1124/mol.106.029686
Brante P. Sampey
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David L. Carbone
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Jonathan A. Doorn
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Derek A. Drechsel
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Dennis R. Petersen
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Abstract

4-Hydroxy-2-nonenal (4-HNE) is a major lipid peroxidation (LPO) product formed during oxidative stress. 4-HNE is highly reactive toward cellular nucleophiles and is implicated in the evolution of numerous pathologies associated with oxidative stress and LPO. Recent evidence suggests that chronic prooxidant exposure results in the loss of extracellular signal-regulated kinase (Erk)-1/2 phosphorylation in vivo, a signaling pathway associated with cellular proliferation, survival, and homeostasis. Immunodetection and molecular analysis were used in this study to evaluate the hypothesis that 4-HNE modification of Erk-1/2 inhibits constitutive Erk-Est-like protein (Elk)-1-activating protein (AP)-1 signaling. Primary rat hepatocytes treated with subcytotoxic, pathologically relevant concentrations of 4-HNE demonstrated a concentration-dependent loss of constitutive Erk-1/2 phosphorylation, activity, and nuclear localization. These findings were consistent with iron-induced intracellular LPO, which also resulted in a concentration-dependent decrease in hepatocyte Erk-1/2 phosphorylation and activity. 4-HNE and iron-induced inhibition of Erk-1/2 was inversely correlated with the accumulation of 4-HNE-Erk-1/2 monomer adducts. 4-HNE treatment of hepatocytes decreased nuclear total and phosphorylated Erk-1/2, Elk-1, and AP-1 phosphorylation as well as cFos and cJun activities. The cytosolic modification of unphosphorylated Erk-1/2 was evaluated in vitro using molar ratios of inactive Erk-2 to 4-HNE consistent with increasing oxidative stress in vivo. Liquid chromatography combined with tandem mass spectrometry confirmed monomer adduct formation and identified the major adduct species at the histidine 178 residue within the kinase phosphorylation lip. These novel results show that the formation of 4-HNE-Erk-1/2 monomer-adducts results in the inhibition of Erk-Elk-AP-1 signaling in hepatocytes and implicates the His 178 residue with the mechanism of inhibition.

Footnotes

  • This work was supported in part by National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism grant R01-AA09300 (to D.R.P.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.029686.

  • ABBREVIATIONS: 4-HNE, 4-hydroxy-2-nonenal; Erk, extracellular signal-regulated kinase; AP, activating protein; Elk, Est-like protein; LPO, lipid peroxidation; LC, liquid chromatography; MS.MS, tandem mass spectrometry; ECM, extracellular matrix; FeAsc, iron ascorbate; LDH, lactate dehydrogenase; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; IP, immunoprecipitate(ed); TRE, 12-O-tetradecanoylphorbol-13-acetate-responsive element; TPA, 12-O-tetradecanoylphorbol-13-acetate; aa, amino acids.

    • Received August 5, 2006.
    • Accepted December 12, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (3)
Molecular Pharmacology
Vol. 71, Issue 3
1 Mar 2007
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Research ArticleArticle

4-Hydroxy-2-nonenal Adduction of Extracellular Signal-Regulated Kinase (Erk) and the Inhibition of Hepatocyte Erk-Est–Like Protein-1-Activating Protein-1 Signal Transduction

Brante P. Sampey, David L. Carbone, Jonathan A. Doorn, Derek A. Drechsel and Dennis R. Petersen
Molecular Pharmacology March 1, 2007, 71 (3) 871-883; DOI: https://doi.org/10.1124/mol.106.029686

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Research ArticleArticle

4-Hydroxy-2-nonenal Adduction of Extracellular Signal-Regulated Kinase (Erk) and the Inhibition of Hepatocyte Erk-Est–Like Protein-1-Activating Protein-1 Signal Transduction

Brante P. Sampey, David L. Carbone, Jonathan A. Doorn, Derek A. Drechsel and Dennis R. Petersen
Molecular Pharmacology March 1, 2007, 71 (3) 871-883; DOI: https://doi.org/10.1124/mol.106.029686
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