This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, B. Articles by Schaffner, W. Search for Related Content PubMed PubMed Citation Articles by Zhang, B. Articles by Schaffner, W.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2003, p. 8471-8485, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8471-8485.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Activity of Metal-Responsive Transcription Factor 1 by Toxic Heavy Metals and H₂O₂ In Vitro Is Modulated by Metallothionein

Bo Zhang,¹ Oleg Georgiev,¹ Michael Hagmann,¹ Çagatay Günes,^1, Mirjam Cramer,¹ Peter Faller,^2, Milan Vasák,² and Walter Schaffner^1*

Institut für Molekularbiologie,¹ Biochemisches Institut, Universität Zürich, CH-8057 Zürich, Switzerland²

Received 27 May 2003/ Returned for modification 16 July 2003/ Accepted 25 August 2003

Metallothioneins are small, cysteine-rich proteins that avidly bind heavy metals such as zinc, copper, and cadmium to reduce their concentration to a physiological or nontoxic level. Metallothionein gene transcription is induced by several stimuli, notably heavy metal load and oxidative stress. Transcriptional induction of metallothionein genes is mediated by the metal-responsive transcription factor 1 (MTF-1), an essential zinc finger protein that binds to specific DNA motifs termed metal-response elements. In cell-free DNA binding reactions with nuclear extracts, MTF-1 requires elevated zinc concentrations for efficient DNA binding but paradoxically is inactivated by other in vivo inducers such as cadmium, copper, and hydrogen peroxide. Here we have developed a cell-free, MTF-1-dependent transcription system which accurately reproduces the activation of metallothionein gene promoters not only by zinc but also by these other inducers. We found that while transcriptional induction by zinc can be achieved by elevated zinc concentration alone, induction by cadmium, copper, or H₂O₂ additionally requires the presence of zinc-saturated metallothionein. This is explained by the preferential binding of cadmium or copper to metallothionein or its oxidation by H₂O₂; the concomitant release of zinc in turn leads to the activation of transcription factor MTF-1. Conversely, thionein, the metal-free form of metallothionein, inhibits activation of MTF-1. The release of zinc from cellular components, including metallothioneins, and the sequestration of zinc by newly produced apometallothionein might be a basic mechanism to regulate MTF-1 activity upon cellular stress.

Present address: Heinrich-Pette-Institut, Abteilung Tumorvirologie, D-20251 Hamburg, Germany.

Present address: Institut für Biologie II/Biochemie, University of Freiburg, D-79104 Freiburg, Germany.

This article has been cited by other articles:

• Chen, X., Hua, H., Balamurugan, K., Kong, X., Zhang, L., George, G. N., Georgiev, O., Schaffner, W., Giedroc, D. P. (2008). Copper sensing function of Drosophila metal-responsive transcription factor-1 is mediated by a tetranuclear Cu(I) cluster. Nucleic Acids Res 36: 3128-3138 [Abstract] [Full Text]  
• Murphy, B. J., Kimura, T., Sato, B. G., Shi, Y., Andrews, G. K. (2008). Metallothionein Induction by Hypoxia Involves Cooperative Interactions between Metal-Responsive Transcription Factor-1 and Hypoxia-Inducible Transcription Factor-1{alpha}. Mol Cancer Res 6: 483-490 [Abstract] [Full Text]  
• Richie, D. L., Fuller, K. K., Fortwendel, J., Miley, M. D., McCarthy, J. W., Feldmesser, M., Rhodes, J. C., Askew, D. S. (2007). Unexpected Link between Metal Ion Deficiency and Autophagy in Aspergillus fumigatus. Eukaryot Cell 6: 2437-2447 [Abstract] [Full Text]  
• Kobayashi, K., Kuroda, J., Shibata, N., Hasegawa, T., Seko, Y., Satoh, M., Tohyama, C., Takano, H., Imura, N., Sakabe, K., Fujishiro, H., Himeno, S. (2007). Induction of Metallothionein by Manganese Is Completely Dependent on Interleukin-6 Production. J. Pharmacol. Exp. Ther. 320: 721-727 [Abstract] [Full Text]  
• Chung, M. J., Hogstrand, C., Lee, S.-J. (2006). Cytotoxicity of nitric oxide is alleviated by zinc-mediated expression of antioxidant genes.. Exp. Biol. Med. 231: 1555-1563 [Abstract] [Full Text]  
• Chicault, C., Toutain, B., Monnier, A., Aubry, M., Fergelot, P., Treut, A. L., Galibert, M.-D., Mosser, J. (2006). Iron-related transcriptomic variations in CaCo-2 cells, an in vitro model of intestinal absorptive cells. Physiol. Genomics 26: 55-67 [Abstract] [Full Text]  
• Li, Y., Kimura, T., Laity, J. H., Andrews, G. K. (2006). The Zinc-Sensing Mechanism of Mouse MTF-1 Involves Linker Peptides between the Zinc Fingers. Mol. Cell. Biol. 26: 5580-5587 [Abstract] [Full Text]  
• Kropat, J., Tottey, S., Birkenbihl, R. P., Depege, N., Huijser, P., Merchant, S. (2005). A regulator of nutritional copper signaling in Chlamydomonas is an SBP domain protein that recognizes the GTAC core of copper response element. Proc. Natl. Acad. Sci. USA 102: 18730-18735 [Abstract] [Full Text]  
• Kennette, W., Collins, O. M., Zalups, R. K., Koropatnick, J. (2005). Basal and Zinc-Induced Metallothionein in Resistance to Cadmium, Cisplatin, Zinc, and tertButyl Hydroperoxide: Studies Using MT Knockout and Antisense-Downregulated MT in Mammalian Cells. Toxicol Sci 88: 602-613 [Abstract] [Full Text]  
• Magda, D., Lecane, P., Miller, R. A., Lepp, C., Miles, D., Mesfin, M., Biaglow, J. E., Ho, V. V., Chawannakul, D., Nagpal, S., Karaman, M. W., Hacia, J. G. (2005). Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines. Cancer Res. 65: 3837-3845 [Abstract] [Full Text]  
• Liu, T., Nakashima, S., Hirose, K., Shibasaka, M., Katsuhara, M., Ezaki, B., Giedroc, D. P., Kasamo, K. (2004). A Novel Cyanobacterial SmtB/ArsR Family Repressor Regulates the Expression of a CPx-ATPase and a Metallothionein in Response to Both Cu(I)/Ag(I) and Zn(II)/Cd(II). J. Biol. Chem. 279: 17810-17818 [Abstract] [Full Text]  
• Chen, X., Zhang, B., Harmon, P. M., Schaffner, W., Peterson, D. O., Giedroc, D. P. (2004). A Novel Cysteine Cluster in Human Metal-responsive Transcription Factor 1 Is Required for Heavy Metal-induced Transcriptional Activation in Vivo. J. Biol. Chem. 279: 4515-4522 [Abstract] [Full Text]  
• Rutherford, J. C., Bird, A. J. (2004). Metal-Responsive Transcription Factors That Regulate Iron, Zinc, and Copper Homeostasis in Eukaryotic Cells. Eukaryot Cell 3: 1-13 [Full Text]  
• Mattie, M. D., Freedman, J. H. (2004). Copper-inducible transcription: regulation by metal- and oxidative stressresponsive pathways. Am. J. Physiol. Cell Physiol. 286: C293-C301 [Abstract] [Full Text]