Rac and p38 kinase mediate 5-lipoxygenase translocation and cell death.
5-Lipoxygenase (5-LO) is a key enzyme involved in the synthesis of leukotrienes from arachidonic acid, and its activation is usually followed by translocation to the nuclear envelope. The details of mechanisms involved in the translocation of 5-LO are not well understood, though Ca(2+) is known to be essential. Here we show that ionomycin, a Ca(2+) ionophore, induces 5-LO translocation and necrotic cell death in Rat-2 fibroblasts, suggesting a potential relationship between activation of 5-LO and cell death. These effects were markedly attenuated in Rat2-Rac(N17) cells expressing a dominant negative Rac1 mutant. Pretreatment with SB203580, a specific inhibitor of p38 MAP kinase, or EGTA, a Ca(2+) chelator, likewise diminished ionomycin-induced 5-LO translocation and cell death, but PD98059, a MEK inhibitor, did not. Thus, Rac and p38 MAP kinase appear to be components in a Ca(2+)-dependent pathway leading to 5-LO translocation and necrotic cell death in Rat-2 fibroblasts.
Eom
Y W
YW
Department of Life Science, Kwangju Institute of Science and Technology, Kwang-Ju, 500-712, Korea.
Cho
S H
SH
Hwang
J S
JS
Yoon
S B
SB
Na
D S
DS
Kang
I J
IJ
Kang
S S
SS
Song
W K
WK
Kim
J H
JH
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D006690:Bisbenzimidazole; D016923:Cell Death / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D005799:Genes, Dominant; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009336:Necrosis; D021381:Protein Transport; D051381:Rats; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007476:Ionophores; D015759:Ionomycin; D001094:Arachidonate 5-Lipoxygenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020744:rac GTP-Binding Proteins; D006690:Bisbenzimidazole