title: Transcriptome response to heavy metal stress in Drosophila reveals a new zinc transporter that confers resistance to zinc.
abstract: All organisms are confronted with external variations in trace element abundance. To elucidate the mechanisms that maintain metal homeostasis and protect against heavy metal stress, we have determined the transcriptome responses in Drosophila to sublethal doses of cadmium, zinc, copper, as well as to copper depletion. Furthermore, we analyzed the transcriptome of a metal-responsive transcription factor (MTF-1) null mutant. The gene family encoding metallothioneins, and the ABC transporter CG10505 that encodes a homolog of 'yeast cadmium factor' were induced by all three metals. Zinc and cadmium responses have similar features: genes upregulated by both metals include those for glutathione S-transferases GstD2 and GstD5, and for zinc transporter-like proteins designated ZnT35C and ZnT63C. Several of the metal-induced genes that emerged in our study are regulated by the transcription factor MTF-1. mRNA studies in MTF-1 overexpressing or null mutant flies and in silico search for metal response elements (binding sites for MTF-1) confirmed novel MTF-1 regulated genes such as ferritins, the ABC transporter CG10505 and the zinc transporter ZnT35C. The latter was analyzed in most detail; biochemical and genetic approaches, including targeted mutation, indicate that ZnT35C is involved in cellular and organismal zinc efflux and plays a major role in zinc detoxification.
authors.affiliation: Institute of Molecular Biology, University of Zurich CH-8057 Zurich, Switzerland.
authors.forename: Hasmik
authors.initials: H
authors.lastname: Yepiskoposyan
authors.forename: Dieter
authors.initials: D
authors.lastname: Egli
authors.forename: Tim
authors.initials: T
authors.lastname: Fergestad
authors.forename: Anand
authors.initials: A
authors.lastname: Selvaraj
authors.forename: Carina
authors.initials: C
authors.lastname: Treiber
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
authors.forename: Oleg
authors.initials: O
authors.lastname: Georgiev
authors.forename: Walter
authors.initials: W
authors.lastname: Schaffner
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003300:Copper / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D004351:Drug Resistance; D005293:Ferritins / Q000502:physiology; D020869:Gene Expression Profiling; D049750:Genome, Insect / Q000187:drug effects; D008297:Male; D019216:Metals, Heavy / Q000494:pharmacology*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D015032:Zinc / Q000494:pharmacology*; D000097809:Transcription Factor MTF-1
chemical_list: D018528:ATP-Binding Cassette Transporters; D002104:Cadmium; D027682:Cation Transport Proteins; D003300:Copper; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005293:Ferritins; D019216:Metals, Heavy; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1; C514589:CG10505 protein, Drosophila