title: Single nucleotide in the MTF-1 binding site can determine metal-specific transcription activation.
abstract: Cells respond to changes in environment by shifting their gene expression profile to deal with the new conditions. The cellular response to changes in metal homeostasis is an important example of this. Transition metals such as iron, zinc, and copper are essential micronutrients but other metals such as cadmium are simply toxic. The cell must maintain metal concentrations in a window that supports efficient metabolic function but must also protect against the damaging effects of high concentrations of these metals. One way a cell regulates metal homeostasis is to control genes involved in metal mobilization and storage. Much of this regulation occurs at the level of transcription and the protein most responsible for this is the conserved metal responsive transcription factor 1 (MTF-1). Interestingly, the nature of the changes in the gene expression profile depends on the type of exposure. The cell somehow senses the kind of the metal challenge and responds appropriately. We have been using the Drosophila system to try to understand the mechanism of this metal discrimination. Using genome-wide mapping of MTF-1 binding under different metal stresses we find that, surprisingly, MTF-1 chooses different DNA binding sites depending on the specific nature of the metal insult. We also find that the type of binding site chosen is an important component of the capability to induce the metal-specific transcription activation.
authors.affiliation: Department of Biology, Brandeis University, Waltham, MA 02454, USA.
authors.forename: Hillel I
authors.initials: HI
authors.lastname: Sims
authors.forename: Gung-Wei
authors.initials: GW
authors.lastname: Chirn
authors.forename: Michael T
authors.initials: MT
authors.lastname: Marr
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002104:Cadmium / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics; D002460:Cell Line; D003300:Copper / Q000494:pharmacology; D000079923:Copper Transporter 1; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D047468:Immunoprecipitation; D008668:Metallothionein / Q000235:genetics; D008670:Metals / Q000494:pharmacology*; D059372:Nucleotide Motifs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D000097809:Transcription Factor MTF-1
chemical_list: D002104:Cadmium; D027682:Cation Transport Proteins; D003300:Copper; D000079923:Copper Transporter 1; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D008668:Metallothionein; D008670:Metals; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1