Abstract
Activation of the aryl hydrocarbon receptor (AHR) by agonists and environmental contaminants like dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) leads to many adverse biological effects, including tumor promotion. With this in mind, we propose that agents that block the AHR pathway may be therapeutically beneficial, particularly by exhibiting chemopreventive activities. In our current research, we have focused on the development of an AHR antagonist using a chemical genetic approach called PROTACS (PROteolysis-TArgeting Chimeric moleculeS). PROTACS is a novel approach of tagging small recognition sequences of a specific E3 ubiquitin ligase complex to a known ligand for the receptor of interest (AHR) for targeting its degradation. Here, we present the design and initial characterization of AHR targeting PROTACS (Apigenin-Protac) designed to degrade and inhibit the AHR in epithelial cells. Our results demonstrate the “proof of concept” of this approach in effectively blocking AHR activity in cultured cells.
Footnotes
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This work was supported by National Institutes of Health grants ES11295, ES08088, and ES80422.
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ABBREVIATIONS: AHR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; MNF, 3′-methoxy-4′-nitroflavone; NHK, normal primary human keratinocyte; PROTACS, Proteolysis-targeting chimeric molecules; and TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; DRE, dioxin response element; DMSO, dimethyl sulfoxide; RT, reverse transcriptase; PCR, polymerase chain reaction; ANOVA, analysis of variance; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; EMSA, electrophoretic mobility shift assay.
- Received August 10, 2007.
- Accepted January 3, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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