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J.Health Sci., 55(1), 72-76, 2009
Metal Response Element-binding Transcription Factor-1 Is Activated by Degradation of Metallothionein
Tomoki Kimura,a Fumika Okumura,a
Ikuyo Oguro,b Tsuyoshi Nakanishi,b, 1
Tomomichi Sone,a Masakazu Isobe,a
Keiichi Tanakab, 2 and Norio Itoh*, b
aDepartment of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101 Japan and
bDepartment of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
1Present address: Laboratory of Hygienics, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585
2Present address: Laboratory of Toxicology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540
Cytosolic zinc-binding protein, metallothionein (MT), is normally saturated with Zn. It is thought that Zn-saturated MT (Zn-MT) acts as a major intracellular Zn pool. Metal-response element-binding transcription factor-1 (MTF-1) plays an important role in Zn-mediated MT transcription. Here, we showed that degradation of Zn-MT activates MTF-1. We measured activated MTF-1 using an electrophoretic mobility shift assay. Interleukin-6 induced MT expression and increased MTF-1 activity. MTF-1 activation was not observed in MT-overexpressing cells. MT-dependent MTF-1 activation was observed only after treating MT-overexpressing cells with cycloheximide (CHX), a protein synthesis inhibitor. CHX-treatment increased the degradation/synthesis ratio of protein. An increase in the degradation/synthesis ratio for the MT protein is expected to increase the level of labile Zn and activate MTF-1. Recombinant MTF-1 was activated by H2O2 only in the presence of Zn-MT. Oxidative stress activated MTF-1 DNA-binding activity in primary cultured hepatocytes but not in MT-deficient hepatocytes. These findings suggest that degradation of Zn-MT activates MTF-1, and that MT plays an important role in zinc-mediated signal transduction.
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