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Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway

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Abstract

Overexpression of epidermal growth factor receptor (EGFR) and establishment of transforming growth factor α (TGF α)/EGF autocrine system are frequently detected in tumor cells. In addition to mitogenic ability, we demonstrate in this report that EGF protects a human esophageal carcinoma (CE) cell line, CE81T/VGH, from staurosporine-induced apoptosis. The anti-apoptotic signal of EGF is alleviated by a MEK inhibitor PK98059 or an ERK2 dominant negative mutant but not by a phosphatidylinositol-3′-kinase (PI-3K) inhibitor wortmannin. Furthermore, v-raf blocks apoptosis induced by staurosporine. This evidence implies that the survival signal of EGF is mediated via the Raf-MEK-ERK pathway but not the PI3-K pathway. The survival effect of EGF is coincident with the induction of mcl-1, an anti-apoptotic gene in the bcl-2 family. PD98059 also suppresses the induction of Mcl-1 by EGF, implying that EGF may up-regulate Mcl-1 via the MAP kinase pathway. Overexpression of mcl-1 is sufficient to protect against apoptosis, while transfection of a mcl-1 antisense plasmid causes cell death. The expression of mcl-1 antisense plasmid also suppresses the anti-apoptotic effect of EGF. Taken together, these results indicate that EGF may up-regulate Mcl-1 through the MAP kinase pathway to suppress apoptosis.

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Acknowledgements

We thank Dr Hsin-Fang Yang-Yen, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Dr Hsian-Fu Kung, NCI-Frederick Cancer Research and Development Center, Frederick, and Dr Melanie H Cobb, University of Texas, Southwestern Medical Center, Dallas, for their generously provided plasmids. We appreciate Dr Chi-Hung Lin, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, for his excellent technical advice in the photography of double staining. We thank Ms Wen-Hsuang Fong for her assistance in the construction of mcl-1 antisense plasmid. We also thank Dr Chen-Kung Chou, Department of Medical Research and Education, Veterans General Hospital, Taipei, Taiwan and Dr Ming-Zong Lai, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, for their inspirational suggestions. We thank Dr Jeou-Yuan Chen for her critical review and suggestions in the preparation of the manuscript and Ms Shiang-Lien Lu for her excellent secretarial assistance. This work was supported by the National Science Council, grants NSC86-2314-B-075-031, NSC87-2314-B-075-061, and NSC88-2314-B-075-013.

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Authors and Affiliations

  1. Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, Republic of China

    Cheun-Miin Leu, Chungming Chang & Cheng-po Hu

  2. Department of Medical Research and Education, Veterans General Hospital, Taipei, Taiwan, Republic of China

    Cheng-po Hu

  3. Intramural Research Affairs, National Health Research Institute, Taipei, Taiwan, Republic of China

    Chungming Chang

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Leu, CM., Chang, C. & Hu, Cp. Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway. Oncogene 19, 1665–1675 (2000). https://doi.org/10.1038/sj.onc.1203452

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