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

The purpose of this study was to evaluate whether the mitogen-activated pro tein kinase (MAPK) signaling pathway contributes to 12-O-tetradecanoylphorb ol-13-acetate (TPA)-induced mononuclear differentiation in the human myelob lastic leukemia ML-1 cells. Upon TPA treatment, the activity of ERK1 and ER K2 rapidly increased, with maximal induction between 1 and 3 h, while ERK2 protein levels remained constant, The activity of JNK1 was also significant ly induced, with JNK1 protein levels increasing moderately during exposure to TPA. Treatment of cells with PD98059, a specific inhibitor of mitogen-ac tivated protein kinase kinase (MEK), inhibited TPA-induced ERK2 activity. F urthermore, PD98059 completely blocked the TPA-induced differentiation of M L-1 cells, as assessed by a number of features associated with mononuclear differentiation including changes in morphology, nonspecific esterase activ ity, phagocytic ability, NADPH oxidase activity, mitochondrial respiration, and c-jun mRNA inducibility. We conclude that activation of the MEK/ERK si gnaling pathway is necessary for TPA-induced mononuclear cell differentiati on.