Soluble receptor proteins are essential mediators of the biological responses produced by certain xenobiotics, i.e. halogenated or non-halogenated polycyclic aromatic hydrocarbons. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent agonists known today both for these receptor-mediated biological responses and for receptor binding itself. The chlorinated dibenzodioxins are formed as unwanted contaminants in the synthesis of halogenated phenols and as incomplete combustion products of organic chlorinated compounds. TCDD itself appears to be one of the most toxic and teratogenic synthetic low-molecular compounds known. The knowledge about a receptor mechanism for the action of TCDD offers one possible strategy for research on the biological mechanisms behind TCDD toxicity. In this context it is of great interest that the receptor mechanism for dioxin action appears to be so similar to the receptor mechanism for steroid hormone action. We propose to study in-depth the biochemistry and molecular biology of the receptor for TCDD as a means to achieve a better understanding of molecular mechanisms of TCDD toxicity. More specifically, we propose to purify the receptor and to study the structural requirements for ligand-receptor interaction, to study TCDD receptor-DNA interaction in order to understand the mechanism behind stimulation of gene expression by TCDD and to isolate and clone TCDD receptor cDNA and gene. Our experience from similar work with the glucocorticoid receptor (we have purified the receptor and have developed monoclonal antibodies against it; recently we have also cloned the receptor cDNA) should help us to fulfil these goals and will also make it possible to perform the proposed studies on a comparative basis in relation to the steroid hormone receptor system.
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