title: Transcriptional regulation of xenobiotic detoxification in Drosophila.
abstract: Living organisms, from bacteria to humans, display a coordinated transcriptional response to xenobiotic exposure, inducing enzymes and transporters that facilitate detoxification. Several transcription factors have been identified in vertebrates that contribute to this regulatory response. In contrast, little is known about this pathway in insects. Here we show that the Drosophila Nrf2 (NF-E2-related factor 2) ortholog CncC (cap 'n' collar isoform-C) is a central regulator of xenobiotic detoxification responses. A binding site for CncC and its heterodimer partner Maf (muscle aponeurosis fibromatosis) is sufficient and necessary for robust transcriptional responses to three xenobiotic compounds: phenobarbital (PB), chlorpromazine, and caffeine. Genetic manipulations that alter the levels of CncC or its negative regulator, Keap1 (Kelch-like ECH-associated protein 1), lead to predictable changes in xenobiotic-inducible gene expression. Transcriptional profiling studies reveal that more than half of the genes regulated by PB are also controlled by CncC. Consistent with these effects on detoxification gene expression, activation of the CncC/Keap1 pathway in Drosophila is sufficient to confer resistance to the lethal effects of the pesticide malathion. These studies establish a molecular mechanism for the regulation of xenobiotic detoxification in Drosophila and have implications for controlling insect populations and the spread of insect-borne human diseases.
authors: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
authors: Jyoti R
authors: JR
authors: Misra
authors: Michael A
authors: MA
authors: Horner
authors: Geanette
authors: G
authors: Lam
authors: Carl S
authors: CS
authors: Thummel
mesh_terms: D000818:Animals; D001665:Binding Sites; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072472:Cytochrome P450 Family 6; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008658:Inactivation, Metabolic; D007306:Insecticides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008294:Malathion / Q000493:pharmacokinetics / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015262:Xenobiotics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D029721:Drosophila Proteins; D007306:Insecticides; D047908:Intracellular Signaling Peptides and Proteins; C527886:Keap1 protein, Drosophila; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; C109499:Cyp6a2 protein, Drosophila; D000072472:Cytochrome P450 Family 6; D008294:Malathion