Resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and abnormal liver development in mice carrying a mutation in the nuclear localization sequence of the aryl hydrocarbon receptor.
The Ah receptor (AHR) mediates the metabolic adaptation to a number of planar aromatic chemicals. Essential steps in this adaptive mechanism include AHR binding of ligand in the cytosol, translocation of the receptor to the nucleus, dimerization with the Ah receptor nuclear translocator, and binding of this heterodimeric transcription factor to dioxin-responsive elements (DREs) upstream of promoters that regulate the expression of genes involved in xenobiotic metabolism. The AHR is also involved in other aspects of mammalian biology, such as the toxicity of molecules like 2,3,7,8-tetrachlorodibenzo-p-dioxin as well as regulation of normal liver development. In an effort to test whether these additional AHR-mediated processes require a nuclear event, such as DRE binding, we used homologous recombination to generate mice with a mutation in the AHR nuclear localization/DRE binding domain. These Ahr(nls) mice were found to be resistant to all 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxic responses that we examined, including hepatomegaly, thymic involution, and cleft palate formation. Moreover, aberrations in liver development observed in these mice were identical to that observed in mice harboring a null allele at the Ahr locus. Taken in sum, these data support a model where most, if not all, of AHR-regulated biology requires nuclear localization.
Bunger
Maureen K
MK
McArdle Laboratory for Cancer Research and the Training Program in Environmental Toxicology, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
Moran
Susan M
SM
Glover
Edward
E
Thomae
Tami L
TL
Lahvis
Garet P
GP
Lin
Bernice C
BC
Bradfield
Christopher A
CA
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005347:Fibroblasts / Q000378:metabolism; D018390:Gene Targeting; D005822:Genetic Vectors; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D019913:Nuclear Localization Signals; D009841:Oligonucleotides / Q000737:chemistry; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013723:Teratogens / Q000633:toxicity; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D008024:Ligands; D019913:Nuclear Localization Signals; D009841:Oligonucleotides; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D013723:Teratogens