Regulation of metallothionein genes by heavy metals appears to be mediated by a zinc-sensitive inhibitor that interacts with a constitutively active transcription factor, MTF-1.
A construct, MRE-beta Geo, with five metal response elements fused to a selectable reporter gene was transfected into BHK cells and a stable clone that could be induced up to 100-fold by zinc, cadmium, bismuth, silver, cobalt, copper, mercury, or nickle was isolated. Some, and perhaps all, of these metals induce MRE-beta Geo by displacing zinc. Transfection of these cells with a construct encoding the transcriptional activator MTF-1 resulted in constitutive expression of MRE-beta Geo, whereas expression of an antisense MTF-1 construct in these cells prevented induction by all of the metals. A variant cell line with high constitutive expression in the absence of added metals was isolated; normal regulation was restored by cell fusion. These results suggest that regulation of metallothionein genes by metals is mediated by MTF-1 interacting with metal response elements and that zinc functions to release MTF-1 from an inhibitor.
Palmiter
R D
RD
Howard Hughes Medical Institute, University of Washington, Seattle 98195.
D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics*; D008670:Metals / Q000494:pharmacology*; D008957:Models, Genetic; D016372:RNA, Antisense / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D013045:Species Specificity; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015032:Zinc / Q000494:pharmacology*; D000097809:Transcription Factor MTF-1
D003513:Cycloheximide; D004268:DNA-Binding Proteins; D008668:Metallothionein; D008670:Metals; D016372:RNA, Antisense; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1