Rac and p38 kinase mediate 5-lipoxygenase translocation and cell death

5-Lipoxygenase (5-LO) is a key enzyme involved in the synthesis of leukotri enes from arachidonic acid, and its activation is usually followed by trans location to the nuclear envelope. The details of mechanisms involved in the translocation of 5-LO are not well understood, though Ca2+ is known to be essential. Here we show that ionomycin, a Ca2+ ionophore, induces 5-LO tran slocation and necrotic cell death in Rat-2 fibroblasts, suggesting a potent ial relationship between activation of 5-LO and cell death. These effects w ere markedly attenuated in Rat2-Rac(N17) cells expressing a dominant negati ve Rad mutant. Pretreatment with SB203580, a specific inhibitor of p38 MAP kinase, or EGTA, a Ca2+ chelator, likewise diminished ionomycin-induced 5-L O translocation and cell death, but PD98059, a MEK inhibitor, did not. Thus , Rac and p38 MAP kinase appear to be components in a Ca2+ dependent pathwa y leading to 5-LO translocation and necrotic cell death in Rat-2 fibroblast s. (C) 2001 Academic Press.