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Title: Phorbol ester-induced mononuclear cell differentiation is blocked by the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059.

Authors: He, H; Wang, X; Gorospe, M; Holbrook, N J; Trush, M A

Published In Cell Growth Differ, (1999 May)

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.

PubMed ID: 10359012 Exiting the NIEHS site

MeSH Terms: Ca(2+)-Calmodulin Dependent Protein Kinase/antagonists & inhibitors; Ca(2+)-Calmodulin Dependent Protein Kinase/biosynthesis; Cell Differentiation/drug effects; Enzyme Activation; Enzyme Inhibitors/pharmacology*; Flavonoids/pharmacology*; Humans; JNK Mitogen-Activated Protein Kinases; Leukocytes, Mononuclear/cytology*; Leukocytes, Mononuclear/drug effects; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases*; Mitogens/pharmacology; Protein Kinase Inhibitors; Protein Kinases/metabolism*; Proto-Oncogene Proteins c-fos/genetics; Proto-Oncogene Proteins c-jun/genetics; RNA, Messenger; Research Support, U.S. Gov't, P.H.S.; Signal Transduction*; Tetradecanoylphorbol Acetate/pharmacology; Tumor Cells, Cultured

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