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KM Dolwick, JV Schmidt, LA Carver, HI Swanson and CA Bradfield
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611.
In this report, we describe the cloning and expression of a cDNA encoding a human Ah receptor, a basic/helix-loop-helix protein that mediates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin. A comparison of this human cDNA with a murine homologue (Ahb1 allele) indicates that the molecular mass variation observed between the receptors found in these two species results from hypervariability of amino acid sequences in the carboxyl termini (< 60% conserved over 450 amino acids). Differential usage of stop codons generates proteins with molecular masses that differ by 6 kDa. In contrast, the amino-terminal halves of these proteins are highly conserved and show 90% amino acid sequence identity. Northern blot analysis indicates that the human Ah receptor mRNA is expressed at its highest levels in placenta and is also highly expressed in lung, heart, pancreas, and liver, with lower levels of expression found in brain, kidney, and skeletal muscle. Expression of the human cDNA in a rabbit reticulocyte lysate system allowed functional analysis of ligand binding, agonist-induced and Ah receptor nuclear translocator-dependent DNA binding, and receptor stabilization by sodium molybdate.
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