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Molecular Pharmacology

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Research ArticleArticle

Selective Activation of the c-Jun N-Terminal Protein Kinase Pathway during 4-Hydroxynonenal-Induced Apoptosis of PC12 Cells

Yunjo Soh, Kyu-Shik Jeong, Insong James Lee, Myung-Ae Bae, Yong-Chul Kim and Byoung J. Song
Molecular Pharmacology September 2000, 58 (3) 535-541; DOI: https://doi.org/10.1124/mol.58.3.535
Yunjo Soh
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Kyu-Shik Jeong
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Insong James Lee
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Myung-Ae Bae
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Yong-Chul Kim
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Byoung J. Song
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Abstract

The by-product of lipid peroxidation, 4-hydroxynonenal (HNE), was shown to cause apoptosis in PC12 cells. In this study, we investigated the molecular mechanism of HNE-induced apoptosis in these cells. Specifically, we determined the effect of HNE on the activities of mitogen-activated protein (MAP) kinases involved in early signal transduction. Within 15 to 30 min after HNE treatment, c-Jun N-terminal protein kinase (JNK) was maximally activated, before it returned to control level at 1 h post-treatment. In contrast, activities of extracellular signal-regulated kinase and p38 MAP kinase remained unchanged from their baseline levels. Stress-activated protein kinase kinase (SEK1), an upstream kinase of JNK, was also activated within 5 min after HNE treatment and remained activated for up to 60 min. Marked activation of the JNK pathway through SEK1 and apoptosis signal-regulating kinase 1 (ASK1), an upstream kinase of SEK1, was demonstrated by the transient transfection of cDNA for wild-type SEK1 or ASK1 together with JNK into COS-7 cells. Furthermore, significant reductions in JNK activation and HNE-induced cell death were observed when either of the dominant negative mutant of SEK1 or ASK1 was cotransfected with JNK. Pretreatment of PC12 cells with a survival-promoting agent, 8-(4-chlorophenylthio)-cAMP, prevented both the HNE-induced JNK activation and apoptosis. Nonaldehyde, a nontoxic aldehyde, neither caused apoptosis nor JNK activation. Pretreatment of PC12 cells with SB203580, a specific inhibitor of p38 MAP kinase, had no effect on HNE-induced apoptosis. All these data suggest that the selective JNK activation by HNE is critical for the apoptosis of PC12 cells and that the HNE-mediated apoptosis is likely to be mediated through the activation of the ASK1-SEK1-JNK pathway without activation of extracellular signal-regulated kinase or p38 MAP kinase.

Footnotes

    • Received December 10, 1999.
    • Accepted May 30, 2000.
  • Send reprint requests to: Byoung J. Song, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 12420 Parklawn Dr., Rm. 425, Rockville, MD 20852. E-mail: bs7t{at}nih.gov

  • ↵1 Both authors contributed equally to the present work.

  • ↵2 Current address: Department of Neuroscience, Graduate School of East-West Medical Science, Kyung-Hee University, Seoul, Korea.

  • ↵3 Current address: Korea Research Institute of Bioscience and Biotechnology, Taejon, Korea.

  • ↵4 Current address: EpiGenesis Pharmaceuticals, Inc., 2005 Eastpark Blvd., Cranbury, NJ.

  • U.S. Government
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Molecular Pharmacology: 58 (3)
Molecular Pharmacology
Vol. 58, Issue 3
1 Sep 2000
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Research ArticleArticle

Selective Activation of the c-Jun N-Terminal Protein Kinase Pathway during 4-Hydroxynonenal-Induced Apoptosis of PC12 Cells

Yunjo Soh, Kyu-Shik Jeong, Insong James Lee, Myung-Ae Bae, Yong-Chul Kim and Byoung J. Song
Molecular Pharmacology September 1, 2000, 58 (3) 535-541; DOI: https://doi.org/10.1124/mol.58.3.535

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Research ArticleArticle

Selective Activation of the c-Jun N-Terminal Protein Kinase Pathway during 4-Hydroxynonenal-Induced Apoptosis of PC12 Cells

Yunjo Soh, Kyu-Shik Jeong, Insong James Lee, Myung-Ae Bae, Yong-Chul Kim and Byoung J. Song
Molecular Pharmacology September 1, 2000, 58 (3) 535-541; DOI: https://doi.org/10.1124/mol.58.3.535
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