Journal
BIOCHEMICAL PHARMACOLOGY
Volume 77, Issue 4, Pages 474-484Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2008.08.034
Keywords
AhR; Dioxin; Estrogen; Cullin 4B; Ubiquitin ligase
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology
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The arylhydrocarbon receptor (AhR) mediates the adverse effects of dioxins, including modulation of sex steroid hormone signaling. The role of AhR as a transcription factor is well described. AhR regulates the expression of target genes such as CYP1A1; however, the mechanisms of AhR function through other target-selective systems remain elusive. Accumulating evidence suggests that AhR modulates the functions of other transcription factors. The ligand-activated AhR directly associates with estrogen or androgen receptors (ER alpha or AR) and modulates their function both positively and negatively. This may, in part explain the sex steroid hormone-related adverse effects of dioxins. AhR has recently been shown to promote the proteolysis of ER alpha/AR through assembling a ubiquitin ligase complex, CUL4-B-AhR. In the CUL4B(AhR) complex, AhR acts as a substrate-recognition subunit to recruit ER alpha/AR. This action defines a novel role for AhR as a ligand-dependent E3 ubiquitin ligase. We propose that target-specific regulation of protein destruction, as well as gene expression, is modulated by environmental toxins through the E3 ubiquitin ligase activity of AhR. (C) 2008 Elsevier Inc. All rights reserved.
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