Numazawa S, Yamada H, Furusho A, Nakahara T, Oguro T, Yoshida T
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Exp Cell Res. 1997 Dec 15;237(2):434-44. doi: 10.1006/excr.1997.3825.
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.
血红素加氧酶-1是一种应激反应酶，与细胞损伤的保护功能有关。我们研究了在人成纤维细胞中，由亚致死浓度的谷胱甘肽耗竭剂（佛尔酮和马来酸二乙酯）诱导血红素加氧酶-1基因表达的细胞事件。谷胱甘肽耗竭剂导致的血红素加氧酶-1 mRNA积累被蛋白质合成抑制剂环己酰亚胺同时处理所消除；然而，当30分钟后添加该抑制剂时，抑制作用减弱。在可诱导的早期反应基因中，c-fos表达在药物处理后30分钟显著升高并达到峰值。用无氧自由基淬灭剂1,4-二氮杂双环[2.2.2]辛烷预处理的细胞中，血红素加氧酶-1和c-fos转录本的积累被消除。谷胱甘肽水平的降低优先激活细胞外信号调节激酶，而不是其他应激激活的蛋白激酶，如c-Jun N端激酶和p38 MAP激酶。用细胞外信号调节激酶级联抑制剂PD 98059或c-fos反义寡脱氧核苷酸预处理细胞，可抑制谷胱甘肽耗竭引起的血红素加氧酶-1诱导。这些观察结果表明，c-Fos蛋白在谷胱甘肽耗竭介导的氧化应激诱导人成纤维细胞血红素加氧酶-1基因表达中起作用。
