Abstract
The purpose of this study was to evaluate whether the mitogen-activated protein kinase (MAPK) signaling pathway contributes to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mononuclear differentiation in the human myeloblastic leukemia ML-1 cells. Upon TPA treatment, the activity of ERK1 and ERK2 rapidly increased, with maximal induction between 1 and 3 h, while ERK2 protein levels remained constant. The activity of JNK1 was also significantly induced, with JNK1 protein levels increasing moderately during exposure to TPA. Treatment of cells with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MEK), inhibited TPA-induced ERK2 activity. Furthermore, PD98059 completely blocked the TPA-induced differentiation of ML-1 cells, as assessed by a number of features associated with mononuclear differentiation including changes in morphology, nonspecific esterase activity, phagocytic ability, NADPH oxidase activity, mitochondrial respiration, and c-jun mRNA inducibility. We conclude that activation of the MEK/ERK signaling pathway is necessary for TPA-induced mononuclear cell differentiation.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
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Cell Differentiation / drug effects
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Enzyme Activation
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Enzyme Inhibitors / pharmacology*
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Flavonoids / pharmacology*
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Humans
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JNK Mitogen-Activated Protein Kinases
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Leukocytes, Mononuclear / cytology*
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Leukocytes, Mononuclear / drug effects
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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 Kinase Kinases
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Mitogen-Activated Protein Kinases*
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Mitogens / pharmacology
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Protein Kinase Inhibitors
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Protein Kinases / metabolism*
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-jun / genetics
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RNA, Messenger
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Signal Transduction*
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Tetradecanoylphorbol Acetate / pharmacology
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Tumor Cells, Cultured
Substances
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Enzyme Inhibitors
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Flavonoids
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Mitogens
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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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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Mitogen-Activated Protein Kinase Kinases
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Tetradecanoylphorbol Acetate
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one