LIGAND AND NUCLEOTIDE SPECIFICITY IN MODULATING ARYL HYDROCARBON RECEPTOR DNA BINDING AND FUNCTIONAL ACTIVITY
The aryl hydrocarbon receptor is a ligand-activated transcription factor which mediates the biological and toxicological effects of a wide variety of structurally dissimilar compounds. The structural diversity of AhR ligands suggests that ligand-specific differences in AhR structure and function could exist, thus leading to ligand-specific differences in AhR-dependent responses. In fact, activation of the AhR by quercetin or 7,12- dimethylbenzaanthracene-3,4-dihydrodiol (DMBA-DHD) reportedly changes the nucleotide specificity of AhR DNA binding. If true, the ability of a chemical to alter the DNA binding specificity of the AhR would be expected to change the spectrum of genes regulated by the AhR and would have significant implications on the biological/toxicological responses of an organism to a complex mixture of structurally diverse AhR agonists. However, detailed gel shift analysis with these ligands failed to demonstrate the ability of these chemicals to stimulate AhR binding to nonclassical, DRE-like response elements. Site-directed mutagenesis studies has also further elucidated those nucleotides necessary for AhR DNA binding and transcriptional activation. Overall, our results do not support the ability of structurally diverse AhR agonists to alter the nucleotide specificity of AhR DNA binding and are consistent with the actions of the activated AhR being mediated by the classical AhR DNA binding consensus.
DeGroot DE Denison MS
Department of Environmental Toxicology,University of California,Davis,CA 95616,USA
国际会议
北京
英文
1-6
2009-08-24（万方平台首次上网日期，不代表论文的发表时间）