Published online 12 October 2005
Article |
Two major branches of anti-cadmium defense in the mouse: MTF-1/metallothioneins and glutathione
Institute of Molecular Biology, University of Zurich Switzerland
*To whom correspondence should be addressed. Tel: +41 44 635 3150; Fax: +41 44 635 6811; Email: walter.schaffner{at}molbio.unizh.ch
Received August 21, 2005. Revised September 17, 2005. Accepted September 17, 2005.
Metal-responsive transcription factor 1 (MTF-1) regulates expression of its target genes in response to various stress conditions, notably heavy metal load, via binding to metal response elements (MREs) in the respective enhancer/promoter regions. Furthermore, it serves a vital function in embryonic liver development. However, targeted deletion of Mtf1 in the liver after birth is no longer lethal. For this study, Mtf1 conditional knockout mice and control littermates were both mock- or cadmium-treated and liver-specific transcription was analyzed. Besides the well-characterized metallothionein genes, several new MTF-1 target genes with MRE motifs in the promoter region emerged. MTF-1 is required for the basal expression of selenoprotein W, muscle 1 gene (Sepw1) that encodes a glutathione-binding and putative antioxidant protein, supporting a role of MTF-1 in the oxidative stress response. Furthermore, MTF-1 mediates the cadmium-induced expression of N-myc downstream regulated gene 1 (Ndrg1), which is induced by several stress conditions and is overexpressed in many cancers. MTF-1 is also involved in the cadmium response of cysteine- and glycine-rich protein 1 gene (Csrp1), which is implicated in cytoskeletal organization. In contrast, MTF-1 represses the basal expression of Slc39a10, a putative zinc transporter. In a pathway independent of MTF-1, cadmium also induced the transcription of genes involved in the synthesis and regeneration of glutathione, a cadmium-binding antioxidant. These data provide strong evidence for two major branches of cellular anti-cadmium defense, one via MTF-1 and its target genes, notably metallothioneins, the other via glutathione, with an apparent overlap in selenoprotein W.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  U. Lindert, M. Cramer, M. Meuli, O. Georgiev, and W. Schaffner Metal-Responsive Transcription Factor 1 (MTF-1) Activity Is Regulated by a Nonconventional Nuclear Localization Signal and a Metal-Responsive Transactivation Domain Mol. Cell. Biol., December 1, 2009; 29(23): 6283 - 6293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Liuzzi, L. Guo, S.-M. Chang, and R. J. Cousins Kruppel-like factor 4 regulates adaptive expression of the zinc transporter Zip4 in mouse small intestine Am J Physiol Gastrointest Liver Physiol, March 1, 2009; 296(3): G517 - G523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Adle and J. Lee Expressional Control of a Cadmium-transporting P1B-type ATPase by a Metal Sensing Degradation Signal J. Biol. Chem., November 14, 2008; 283(46): 31460 - 31468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-S. Ryu, L. A. Lichten, J. P. Liuzzi, and R. J. Cousins Zinc Transporters ZnT1 (Slc30a1), Zip8 (Slc39a8), and Zip10 (Slc39a10) in Mouse Red Blood Cells Are Differentially Regulated during Erythroid Development and by Dietary Zinc Deficiency J. Nutr., November 1, 2008; 138(11): 2076 - 2083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zheng, G. P. Feeney, P. Kille, and C. Hogstrand Regulation of ZIP and ZnT zinc transporters in zebrafish gill: zinc repression of ZIP10 transcription by an intronic MRE cluster Physiol Genomics, July 1, 2008; 34(2): 205 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E.-S. Han, F. L. Muller, V. I. Perez, W. Qi, H. Liang, L. Xi, C. Fu, E. Doyle, M. Hickey, J. Cornell, et al. The in vivo gene expression signature of oxidative stress Physiol Genomics, June 1, 2008; 34(1): 112 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Murphy, T. Kimura, B. G. Sato, Y. Shi, and G. K. Andrews Metallothionein Induction by Hypoxia Involves Cooperative Interactions between Metal-Responsive Transcription Factor-1 and Hypoxia-Inducible Transcription Factor-1{alpha} Mol. Cancer Res., March 1, 2008; 6(3): 483 - 490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Valgardsdottir, I. Chiodi, M. Giordano, A. Rossi, S. Bazzini, C. Ghigna, S. Riva, and G. Biamonti Transcription of Satellite III non-coding RNAs is a general stress response in human cells Nucleic Acids Res., February 2, 2008; 36(2): 423 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Jackson, R. M. Helston, J. A. McKay, E. D. O'Neill, J. C. Mathers, and D. Ford Splice Variants of the Human Zinc Transporter ZnT5 (SLC30A5) Are Differentially Localized and Regulated by Zinc through Transcription and mRNA Stability J. Biol. Chem., April 6, 2007; 282(14): 10423 - 10431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Tu, X. Yan, L. Hood, and B. Lin Proteomics Analysis of the Interactome of N-myc Downstream Regulated Gene 1 and Its Interactions with the Androgen Response Program in Prostate Cancer Cells Mol. Cell. Proteomics, April 1, 2007; 6(4): 575 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Adle, D. Sinani, H. Kim, and J. Lee A Cadmium-transporting P1B-type ATPase in Yeast Saccharomyces cerevisiae J. Biol. Chem., January 12, 2007; 282(2): 947 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yepiskoposyan, D. Egli, T. Fergestad, A. Selvaraj, C. Treiber, G. Multhaup, O. Georgiev, and W. Schaffner Transcriptome response to heavy metal stress in Drosophila reveals a new zinc transporter that confers resistance to zinc Nucleic Acids Res., October 18, 2006; 34(17): 4866 - 4877. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Chung, C. Hogstrand, and S.-J. Lee Cytotoxicity of nitric oxide is alleviated by zinc-mediated expression of antioxidant genes. Experimental Biology and Medicine, October 1, 2006; 231(9): 1555 - 1563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Cousins, J. P. Liuzzi, and L. A. Lichten Mammalian Zinc Transport, Trafficking, and Signals J. Biol. Chem., August 25, 2006; 281(34): 24085 - 24089. [Full Text] [PDF]
|
|
|
|
|
|
D. Egli, H. Yepiskoposyan, A. Selvaraj, K. Balamurugan, R. Rajaram, A. Simons, G. Multhaup, S. Mettler, A. Vardanyan, O. Georgiev, et al. A family knockout of all four Drosophila metallothioneins reveals a central role in copper homeostasis and detoxification. Mol. Cell. Biol., March 1, 2006; 26(6): 2286 - 2296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. B. Aydemir, R. K. Blanchard, and R. J. Cousins Zinc supplementation of young men alters metallothionein, zinc transporter, and cytokine gene expression in leukocyte populations PNAS, February 7, 2006; 103(6): 1699 - 1704. [Abstract] [Full Text] [PDF]
|
|