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.
Numazawa
S
S
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. numazawa@pharm.showa-u.ac.jp
Yamada
H
H
Furusho
A
A
Nakahara
T
T
Oguro
T
T
Yoshida
T
T
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017781:Genes, Immediate-Early; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D006801:Humans; D007659:Ketones / Q000494:pharmacology; D008298:Maleates / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000235:genetics
D005419:Flavonoids; D007659:Ketones; D008298:Maleates; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C018637:phorone; D006419:Heme Oxygenase (Decyclizing); D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C014476:diethyl maleate; D005978:Glutathione; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one