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Molecular Pharmacology

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Research ArticleArticle

Involvement of Asp-Glu-Val-Asp-Directed, Caspase-Mediated Mitogen-Activated Protein Kinase Kinase 1 Cleavage, c-Jun N-Terminal Kinase Activation, and Subsequent Bcl-2 Phosphorylation for Paclitaxel-Induced Apoptosis in HL-60 Cells

Shine-Gwo Shiah, Shuang-En Chuang and Min-Liang Kuo
Molecular Pharmacology February 2001, 59 (2) 254-262; DOI: https://doi.org/10.1124/mol.59.2.254
Shine-Gwo Shiah
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Shuang-En Chuang
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Min-Liang Kuo
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Abstract

Paclitaxel is a novel anticancer drug that has demonstrated efficacy toward treating several malignant tumor types. Here, we demonstrate that c-Jun NH2-terminal kinase (JNK), but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2, was persistently activated by paclitaxel or other microtubule-damaging agents within human leukemia HL-60 cells. Overexpression of a dominant-negative mutant, mitogen-activated protein kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide prevented paclitaxel-induced JNK activation, Bcl-2 phosphorylation and apoptosis. Furthermore, we found that the full-length MEKK1 was cleaved to a 91-kDa carboxyl-terminal fragment at the earlier time of apoptosis induced by microtubule-damaging agents. This cleavage, however, occurred consistently with JNK activation and Bcl-2 phosphorylation, but preceded DNA fragmentation in cells in response to paclitaxel activity. The caspase inhibitor Ac-Asp-Glu-Val-Asp-CHO (DEVD-CHO), but not Ac-Tyr-Val-Ala-Asp-CHO (Ac-YVAD-CHO), effectively blocked MEKK1 cleavage, JNK activation, Bcl-2 phosphorylation, and subsequent apoptosis. Subcellular fractionation revealed that the 91-kDa C-terminal MEKK1 fragment was translocated to cytosol. Notably, the MEKK1 fragment could be coimmunoprecipitated with anti-JNK antibodies, suggesting that a signaling complex of C-terminal MEKK1/stress-activated protein kinase/extracellular-signal regulated kinase 1/JNK formed during apoptosis induced by microtubule-damaging agents. Taken together, our results suggest that disruption of cytoarchitecture by paclitaxel triggers a novel apoptosis-signaling pathway, wherein an active DEVD-directed caspase (DEVDase) initially cleaves MEKK1to generate a proapoptotic kinase fragment that is able to activate JNK and subsequent Bcl-2 phosphorylation, finally eliciting cell death.

Footnotes

    • Received March 10, 2000.
    • Accepted October 22, 2000.
  • Send reprint requests to: Min-Liang Kuo, Ph.D., Laboratory of Molecular and Cellular Toxicology, Institute of Toxciology, College of Medicine, National Taiwan University, No. 1, Sec., 1, Jen-Ai Road, Taipei, Taiwan. E-mail: toxkml{at}ha.mc.ntu.edu.tw

  • This work was supported by National Science Council of Taiwan Grant NSC 89-2320-B-002-015.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (2)
Molecular Pharmacology
Vol. 59, Issue 2
1 Feb 2001
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Involvement of Asp-Glu-Val-Asp-Directed, Caspase-Mediated Mitogen-Activated Protein Kinase Kinase 1 Cleavage, c-Jun N-Terminal Kinase Activation, and Subsequent Bcl-2 Phosphorylation for Paclitaxel-Induced Apoptosis in HL-60 Cells
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Research ArticleArticle

Involvement of Asp-Glu-Val-Asp-Directed, Caspase-Mediated Mitogen-Activated Protein Kinase Kinase 1 Cleavage, c-Jun N-Terminal Kinase Activation, and Subsequent Bcl-2 Phosphorylation for Paclitaxel-Induced Apoptosis in HL-60 Cells

Shine-Gwo Shiah, Shuang-En Chuang and Min-Liang Kuo
Molecular Pharmacology February 1, 2001, 59 (2) 254-262; DOI: https://doi.org/10.1124/mol.59.2.254

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Research ArticleArticle

Involvement of Asp-Glu-Val-Asp-Directed, Caspase-Mediated Mitogen-Activated Protein Kinase Kinase 1 Cleavage, c-Jun N-Terminal Kinase Activation, and Subsequent Bcl-2 Phosphorylation for Paclitaxel-Induced Apoptosis in HL-60 Cells

Shine-Gwo Shiah, Shuang-En Chuang and Min-Liang Kuo
Molecular Pharmacology February 1, 2001, 59 (2) 254-262; DOI: https://doi.org/10.1124/mol.59.2.254
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