Manganese Superoxide Dismutase Is Induced by Endoplasmic Reticulum Stress through IRE1-Mediated Nuclear Factor (NF)-κB and AP-1 Activation
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manganese superoxide dismutase (MnSOD)
endoplasmic reticulum (ER) stress
nuclear factor (NF)-κB
Manganese superoxide dismutase (MnSOD) is an antioxidative enzyme that scavenges superoxide radicals and is localized in the mitochondrial matrix. MnSOD is induced by a variety of stimuli through nuclear factor (NF)-κB and AP-1 activation. We investigated the expression of MnSOD in HeLa cells exposed to various agents interfering with endoplasmic reticulum (ER) functions. All agents caused an increase in the mRNA and protein levels of MnSOD. Although ER stress-responsive genes often are up-regulated by ATF6, IRE1 and XBP1, which are ER stress-related transcription factors/transducers, the overexpression of neither molecule affected the levels of MnSOD mRNA and protein. Furthermore, we showed that ER stress reagents induced NF-κB and AP-1 activation that were inhibited by a dominant-negative IRE1 mutant. We finally demonstrated that ER stress-induced MnSOD expression was reduced by the IRE1 mutant. These results suggest that the MnSOD expression is controlled by ER stress through IRE1-mediated NF-κB and AP-1 activation.
This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technalogy, Japan.
Biological and Pharmaceutical Bulletin
The Pharmaceutical Society of Japan
© 2004 The Pharmaceutical Society of Japan