Abstract
Overexpression of epidermal growth factor receptor (EGFR) and establishment of transforming growth factor alpha (TGF alpha)/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 PD98059 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 antiapoptotic 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Apoptosis / drug effects*
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Apoptosis / genetics
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Carcinoma / genetics
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Carcinoma / pathology
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Cysteine Endopeptidases / physiology*
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Cysteine Proteinase Inhibitors / pharmacology*
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DNA, Antisense / genetics
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Epidermal Growth Factor / pharmacology*
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ErbB Receptors / drug effects
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ErbB Receptors / physiology*
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Esophageal Neoplasms / genetics
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Esophageal Neoplasms / pathology
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Flavonoids / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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MAP Kinase Kinase Kinase 1*
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MAP Kinase Signaling System / drug effects*
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / physiology
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / physiology
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins c-bcl-2*
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Proto-Oncogene Proteins c-raf / physiology
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Recombinant Fusion Proteins / physiology
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Staurosporine / antagonists & inhibitors*
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Transfection
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Tumor Cells, Cultured / drug effects
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Wortmannin
Substances
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Androstadienes
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Cysteine Proteinase Inhibitors
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DNA, Antisense
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Flavonoids
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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Epidermal Growth Factor
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ErbB Receptors
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human
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Cysteine Endopeptidases
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Staurosporine
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin