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.
Lepley
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Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA. robert.lepley@uchsc.edu
Fitzpatrick
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D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000494:pharmacology; D001483:Base Sequence; D001692:Biological Transport / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006098:Granulocytes / Q000201:enzymology*; D018922:HL-60 Cells; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D009685:Nuclear Envelope / Q000201:enzymology; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D016718:Arachidonic Acid; D000001:Calcimycin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D001094:Arachidonate 5-Lipoxygenase; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one