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.

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. Research Abstract Details 

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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. Abstract Text:

Brante P Sampey,David L Carbone,Jonathan A Doorn,Derek A Drechsel,Dennis R Petersen,

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.

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. Publishing Authors By Initials

BP Sampey,DL Carbone,JA Doorn,DA Drechsel,DR Petersen,

For similar proteins: dna-binding proteins: proto-oncogene proteins c-ets: ternary complex factors: ets-domain protein elk-1 research abstracts see: proteins: dna-binding proteins: proto-oncogene proteins c-ets: ternary complex factors: ets-domain protein elk-1 research

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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. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Molecular pharmacology

VOLUME: 71

Page Numbers: 871-83

Journal Abbreviation: Mol. Pharmacol.

ISSN: 0026-895X

DAY: 12

MONTH: 12

YEAR: 2006

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. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 35623

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. Keywords Mesh Terms:

KEYWORDS: ets-Domain Protein Elk-1

MESH TERMS: physiology

Chemical & Substance for Abstract: 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. Information

Substance Name: Extracellular Signal-Regulated MAP Kinas

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for 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.

AFFILIATION: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, School of Pharmacy, Denver, CO 80262, USA.

Country: United States

AGENCY: United States NIAAA

GRANT: R01-AA09300

ACRONYM: AA

MEDLINETA: Mol Pharmacol

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