Inhibition of Mitogen-Activated Protein Kinase Kinase Blocks Activation and Redistribution of 5-Lipoxygenase in HL-60 Cells

In Ca2+ionophore-activated HL-60 granulocytes the mitogen-activated protein kinase kinase-1 inhibitor, PD098059, blocked translocation of 5-lipoxygenase from the cytosol to the nuclear membrane and the corresponding enzyme activation. PD098059 inhibited 5-HETE formation with an IC50= 9.4 μMin cells stimulated with A23187 alone, and with an IC50= 12 μMin cells stimulated with A23187 plus 20 μMarachidonic acid. PD098059 inhibited translocation of 5-lipoxygenase in a concentration-dependent manner with an IC50approximately 10 μM. At concentrations less than 100 μMPD098059 had no effect on purified recombinant 5-LO activity. Collectively, these data indicate that MAPKK-1 participates in the molecular processes governing activation and translocation of 5-lipoxygenase from the cytosol to the nuclear membrane.