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      Transcriptional Induction of Metallothionein by Tris(pentafluorophenyl)stibane in Cultured Bovine Aortic Endothelial Cells

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          Vascular endothelial cells cover the luminal surface of blood vessels and contribute to the prevention of vascular disorders such as atherosclerosis. Metallothionein (MT) is a low molecular weight, cysteine-rich, metal-binding, inducible protein, which protects cells from the toxicity of heavy metals and active oxygen species. Endothelial MT is not induced by inorganic zinc. Adequate tools are required to investigate the mechanisms underlying endothelial MT induction. In the present study, we found that an organoantimony compound, tris(pentafluorophenyl)stibane, induces gene expression of MT-1A and MT-2A, which are subisoforms of MT in bovine aortic endothelial cells. The data reveal that MT-1A is induced by activation of both the MTF-1–MRE and Nrf2–ARE pathways, whereas MT-2A expression requires only activation of the MTF-1–MRE pathway. The present data suggest that the original role of MT-1 is to protect cells from heavy metal toxicity and oxidative stress in the biological defense system, while that of MT-2 is to regulate intracellular zinc metabolism.

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          Most cited references 53

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          Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene.

          Stress response elements, which mediate induction of the mouse heme oxygenase-1 (HO-1) gene by several agents, resemble the binding site for the activator protein-1 (Jun/Fos), Maf, and Cap'n'Collar/basic leucine zipper (CNC-bZIP) families of proteins. In L929 fibroblasts, significant activation of an HO-1 enhancer-reporter fusion gene was observed only with the CNC-bZIP class of proteins with Nrf2 exhibiting the highest level of trans-activation, between 25- and 30-fold. To further examine the role of this factor in HO-1 gene regulation, a dominant-negative mutant, Nrf2M, was generated and conditionally expressed in L929 cells. The mutant protein was detected in cytoplasmic and nuclear fractions but did not affect cell growth. Under conditions of Nrf2M overexpression, HO-1 mRNA accumulation in response to heme, cadmium, zinc, arsenite, and tert-butylhydroquinone was inhibited by 85-95%. In contrast, overexpression of a dominant-negative mutant of c-Jun decreased L929 cell growth but did not inhibit HO-1 gene activation. Nrf2 does not homodimerize, but CNC-bZIP.small Maf protein heterodimers and Nrf2. Jun protein complexes are proposed to function as trans-activators. Co-expression of Jun proteins or p18, however, had no significant affect or inhibited Nrf2-mediated trans-activation. Taken together, these results implicate Nrf2 in the induction of the HO-1 gene but suggest that the Nrf2 partner in this function is a factor other than p18 or Jun proteins.
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              Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium.

              Nrf2 mediates inducer-dependent activation of the heme oxygenase-1 (HO-1) gene (Alam, J., Stewart, D., Touchard, C., Boinapally, S., Choi, A. M., and Cook, J. L. (1999) J. Biol. Chem. 274, 26071-26078), but the mechanism by which HO-1 inducers regulate Nrf2 function is not known. Treatment of mouse hepatoma (Hepa) cells with 50 microm CdCl(2) increased the amount of Nrf2 protein in a time-dependent manner; induction was observed within 30 min, prior to the accumulation of HO-1 mRNA. Cadmium did not significantly affect the steady-state level of Nrf2 mRNA or the initial rate of Nrf2 protein synthesis but increased the half-life of Nrf2 from approximately 13 to 100 min. Proteasome inhibitors, but not other protease inhibitors, enhanced the expression of Nrf2, and ubiquitinylated Nrf2 was detected after proteasome inhibition. Cycloheximide inhibited cadmium-stimulated Nrf2 expression and DNA binding activity and attenuated HO-1 mRNA accumulation. Conversely, proteasome inhibitors enhanced HO-1 mRNA and protein accumulation by a Nrf2-dependent mechanism. Together, these results indicate that Nrf2 is targeted for rapid degradation by the ubiquitin-proteasome pathway and that cadmium delays the rate of Nrf2 degradation leading to ho-1 gene activation.

                Author and article information

                Role: Academic Editor
                Int J Mol Sci
                Int J Mol Sci
                International Journal of Molecular Sciences
                23 August 2016
                September 2016
                : 17
                : 9
                [1 ]Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; t-fujie@ 123456phar.toho-u.ac.jp (T.F.); j3b13674@ 123456ed.tus.ac.jp (M.M.); eyoshida@ 123456rs.tus.ac.jp (E.Y.)
                [2 ]Laboratory of Organic and Medicinal Chemistry, School of Pharmaceutical Sciences, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan
                [3 ]Depertment of Life Science, Faculty of Science and Engineering, Setsunan University, 17-8 Ikedanakamachi, Neyagawa 572-8508, Japan; tomoki@ 123456lif.setsunan.ac.jp
                [4 ]Department of Environmental Health, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392, Japan; yasuyuki@ 123456toyaku.ac.jp
                [5 ]Department of Environmental Health, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan; yamamoto@ 123456phar.toho-u.ac.jp
                Author notes
                [* ]Correspondence: s-yasuik@ 123456dpc.agu.ac.jp (S.Y.); t-kaji@ 123456rs.tus.ac.jp (T.K.); Fax: +81-52-757-6799 (S.Y.); +81-4-7121-3621 (T.K.)
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).



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