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 microM in cells stimulated with A23187 alone, and with an IC50 = 12 microM in cells stimulated with A23187 plus 20 microM arachidonic acid. PD098059 inhibited translocation of 5-lipoxygenase in a concentration-dependent manner with an IC50 approximately 10 microM. At concentrations less than 100 microM PD098059 had no effect on purified recombinant 5-LO activity. Collectively, these data indicate that MAPKK-l participates in the molecular processes governing activation and translocation of 5-lipoxygenase from the cytosol to the nuclear membrane.