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Mitogen-activated protein kinase phosphatase-1 modulated JNK activation is critical for apoptosis induced by inhibitor of epidermal growth factor receptor-tyrosine kinase.
FEBS J. 2009 Mar; 276(5):1255-65.FJ

Abstract

Alterations resulting in enhanced epidermal growth factor receptor (EGFR) expression or function have been documented in a variety of tumors. Therefore, EGFR-tyrosine kinase is a promising therapeutic target. Although in vitro and in vivo studies have shown the anti-tumor activity of EGFR-tyrosine kinase inhibitors against various tumor types, little is known about the mechanism by which such inhibitors effect their anti-tumor action. AG1478 is known to selectively inhibit EGFR-tyrosine kinase. In this study, we showed that AG1478 caused apoptosis and apoptosis-related reactions such as the activation of caspase 3 in human non-small cell lung cancer cell line PC-9. To investigate the signaling route by which AG1478 induced apoptosis, we examined the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase p38 in AG1478-treated PC-9 cells. JNK, but not p38, was significantly activated by AG1478 as determined by both immunoblot analysis for levels of phosphorylated JNK and an in vitro activity assay. Various types of stimuli activated JNK through phosphorylation by the dual-specificity JNK kinases, but the dual-specificity JNK kinases MKK4 and MKK7 were not activated by AG1478 treatment. However, JNK phosphatase, i.e. mitogen-activated protein kinase phosphatase-1 (MKP-1), was constitutively expressed in the PC-9 cells, and its expression level was reduced by AG1478. The inhibition of JNK activation by ectopic expression of MKP-1 or a dominant-negative form of JNK strongly suppressed AG1478-induced apoptosis. These results reveal that JNK, which is activated through the decrease in the MKP-1 level, is critical for EGFR-tyrosine kinase inhibitor-induced apoptosis.

Authors+Show Affiliations

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan. takeuchi@pharm.setsunan.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19175673

Citation

Takeuchi, Kenji, et al. "Mitogen-activated Protein Kinase Phosphatase-1 Modulated JNK Activation Is Critical for Apoptosis Induced By Inhibitor of Epidermal Growth Factor Receptor-tyrosine Kinase." The FEBS Journal, vol. 276, no. 5, 2009, pp. 1255-65.
Takeuchi K, Shin-ya T, Nishio K, et al. Mitogen-activated protein kinase phosphatase-1 modulated JNK activation is critical for apoptosis induced by inhibitor of epidermal growth factor receptor-tyrosine kinase. FEBS J. 2009;276(5):1255-65.
Takeuchi, K., Shin-ya, T., Nishio, K., & Ito, F. (2009). Mitogen-activated protein kinase phosphatase-1 modulated JNK activation is critical for apoptosis induced by inhibitor of epidermal growth factor receptor-tyrosine kinase. The FEBS Journal, 276(5), 1255-65. https://doi.org/10.1111/j.1742-4658.2008.06861.x
Takeuchi K, et al. Mitogen-activated Protein Kinase Phosphatase-1 Modulated JNK Activation Is Critical for Apoptosis Induced By Inhibitor of Epidermal Growth Factor Receptor-tyrosine Kinase. FEBS J. 2009;276(5):1255-65. PubMed PMID: 19175673.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitogen-activated protein kinase phosphatase-1 modulated JNK activation is critical for apoptosis induced by inhibitor of epidermal growth factor receptor-tyrosine kinase. AU - Takeuchi,Kenji, AU - Shin-ya,Tomohiro, AU - Nishio,Kazuto, AU - Ito,Fumiaki, PY - 2009/1/30/entrez PY - 2009/1/30/pubmed PY - 2009/4/9/medline SP - 1255 EP - 65 JF - The FEBS journal JO - FEBS J VL - 276 IS - 5 N2 - Alterations resulting in enhanced epidermal growth factor receptor (EGFR) expression or function have been documented in a variety of tumors. Therefore, EGFR-tyrosine kinase is a promising therapeutic target. Although in vitro and in vivo studies have shown the anti-tumor activity of EGFR-tyrosine kinase inhibitors against various tumor types, little is known about the mechanism by which such inhibitors effect their anti-tumor action. AG1478 is known to selectively inhibit EGFR-tyrosine kinase. In this study, we showed that AG1478 caused apoptosis and apoptosis-related reactions such as the activation of caspase 3 in human non-small cell lung cancer cell line PC-9. To investigate the signaling route by which AG1478 induced apoptosis, we examined the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase p38 in AG1478-treated PC-9 cells. JNK, but not p38, was significantly activated by AG1478 as determined by both immunoblot analysis for levels of phosphorylated JNK and an in vitro activity assay. Various types of stimuli activated JNK through phosphorylation by the dual-specificity JNK kinases, but the dual-specificity JNK kinases MKK4 and MKK7 were not activated by AG1478 treatment. However, JNK phosphatase, i.e. mitogen-activated protein kinase phosphatase-1 (MKP-1), was constitutively expressed in the PC-9 cells, and its expression level was reduced by AG1478. The inhibition of JNK activation by ectopic expression of MKP-1 or a dominant-negative form of JNK strongly suppressed AG1478-induced apoptosis. These results reveal that JNK, which is activated through the decrease in the MKP-1 level, is critical for EGFR-tyrosine kinase inhibitor-induced apoptosis. SN - 1742-4658 UR - https://www.unboundmedicine.com/medline/citation/19175673/Mitogen_activated_protein_kinase_phosphatase_1_modulated_JNK_activation_is_critical_for_apoptosis_induced_by_inhibitor_of_epidermal_growth_factor_receptor_tyrosine_kinase_ DB - PRIME DP - Unbound Medicine ER -