Two major branches of anti-cadmium defense in the mouse: MTF-1/metallothioneins and glutathione.
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.
Wimmer
Ursula
U
Institute of Molecular Biology, University of Zurich, Switzerland.
Wang
Ying
Y
Georgiev
Oleg
O
Schaffner
Walter
W
D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051151:Selenoprotein W; D051140:Selenoproteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000097809:Transcription Factor MTF-1; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D002104:Cadmium; D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005978:Glutathione; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008668:Metallothionein; D009687:Nuclear Proteins; D011506:Proteins; D051151:Selenoprotein W; D051140:Selenoproteins; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C486177:Csrp1 protein, mouse; C557566:ZIP10 protein, mouse