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The Mitogen-Activated Protein Kinase Pathway Inhibits Ceramide-Induced Terminal Differentiation of a Human Monoblastic Leukemia Cell Line, U937¹

Scott J. Ragg^*, Shuji Kaga^*, Karen A. Berg and Atsuo Ochi^2,*,

^* John P. Robarts Research Institute and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada

This communication describes an extracellular signal-regulated kinase kinase (MEK)-dependent signal transduction pathway that prevents the terminal differentiation of a hemopoietic cell line. Both PMA and the cell-permeable ceramide, C₂-ceramide, caused differentiation of U937 cells, but with distinct cell morphology and CD11b/CD14 surface expression. While PMA activated extracellular signal-regulated kinase (ERK), a downstream kinase of Raf-MEK signaling, C₂-ceramide activated c-Jun NH₂-terminal kinase (JNK), an anchor kinase of stress-induced signaling. Furthermore, only C₂-ceramide stimulated an induction of cell cycle arrest that was associated with stable expression of p21^CIP1 and retinoblastoma nuclear phosphoprotein dephosphorylation. Expression of p21^CIP1 and JNK activation were also observed in sphingosine-treated cells, whereas sphingosine did not induce detectable differentiation. Concomitant stimulation with C₂-ceramide and PMA resulted in the PMA phenotype, and cell cycle arrest was absent. ERK activation was enhanced by C₂-ceramide plus PMA stimulation, whereas the activation of JNK was aborted. Strikingly, the inhibition of MEK with PD98059 altered the phenotype of C₂-ceramide- and PMA-stimulated U937 cells to that of cells treated with C₂-ceramide alone. Thus, ERK and JNK pathways deliver distinct signals, and the ERK pathway is dominant to the JNK cascade. Furthermore, differentiation and cell cycle arrest caused by C₂-ceramide rely on independent signaling pathways, and JNK is an unlikely signaling element for this differentiation. Importantly, during C₂-ceramide and PMA costimulation, the JNK pathway is not simply blocked by ERK activation; rather, cross-talk between these MAP kinase pathways acts to simultaneously augment ERK activity and down-regulate JNK activity.

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