Cooperative induction of c-fos and heme oxygenase gene products under oxidative stress in human fibroblastic cells.

Heme oxygenase-1 is a stress responsive enzyme and implicated in a protective function of cellular damage. We investigated cellular events leading to the heme oxygenase-1 gene expression induced by sublethal concentrations of glutathione depletors, phorone and diethyl maleate, in human fibroblastic cells. Accumulation of heme oxygenase-1 mRNA by glutathione depletors was canceled by simultaneous treatment with cycloheximide, an inhibitor of protein synthesis; however, the inhibitory effect decreased when the inhibitor was added 30 min later. Among the inducible early response genes, the c-fos expression was significantly elevated with a peak at 30 min after the agents. Accumulation of heme oxygenase-1 and c-fos transcripts was abrogated in cells pretreated with 1,4-diazabicyclo[2.2.2]octane, an oxygen-free radical quencher. Decrease in glutathione levels preferentially activated extracellular-signal regulated kinases rather than other stress-activated protein kinases such as c-Jun N-terminal kinases and p38 MAP kinase. Pretreatment of cells with PD 98059, an inhibitor of the extracellular-signal regulated kinase cascade, or the c-fos antisense oligodeoxynucleotide inhibited the heme oxygenase-1 induction elicited by glutathione depletion. These observations indicated that c-Fos protein plays a role in heme oxygenase-1 gene expression induced by glutathione depletion-mediated oxidative stress in human fibroblasts.