Dioxin receptor is a ligand-dependent E3 ubiquitin ligase

Abstract

Fat-soluble ligands, including sex steroid hormones and environmental toxins, activate ligand-dependent DNA-sequence-specific transcriptional factors that transduce signals through target-gene-selective transcriptional regulation. However, the mechanisms of cellular perception of fat-soluble ligand signals through other target-selective systems remain unclear. The ubiquitin-proteasome system regulates selective protein degradation, in which the E3 ubiquitin ligases determine target specificity. Here we characterize a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which dioxin receptor (AhR) is integrated as a component of a novel cullin 4B ubiquitin ligase complex, CUL4B(AhR). Complex assembly and ubiquitin ligase activity of CUL4B(AhR) in vitro and in vivo are dependent on the AhR ligand. In the CUL4B(AhR) complex, ligand-activated AhR acts as a substrate-specific adaptor component that targets sex steroid receptors for degradation. Thus, our findings uncover a function for AhR as an atypical component of the ubiquitin ligase complex and demonstrate a non-genomic signalling pathway in which fat-soluble ligands regulate target-protein-selective degradation through a ubiquitin ligase complex.

Aryl hydrocarbon receptor in association with RelA modulates IL-6 expression in non-smoking lung cancer

“…In the nucleus, IkBa will associate with RelA; the complex is then exported out of the nucleus and thus terminates transcriptional activation. Ohtake et al (2007) reported that AhR is an atypical E3 ubiquitin ligase that is required for ubiquitination. Thus, overexpression of AhR in cells might increase the E3 ubiquitin ligase activity of AhR, which, in turn, might reduce IkBa protein levels.…”

Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

“…In LNT-229 cells, 3-MC did not substantially induce CYP1A1 mRNA levels and even lowered them at longer incubation periods of 48 and 72 h (Figure 2e). This response pattern may result from a negative feedback loop of AhR stimulation attributed to the promotion of AHR degradation (Ohtake et al, 2007). AhR gene silencing diminished CYP1A1 mRNA expression in both cell lines (Figure 2f).…”

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

“…For example, inhibition of some E2-responsive genes involves direct interactions of the AhR complex with inhibitory dioxin response elements (iDREs) in the cathepsin D, heat shock protein 27, pS2 and c-fos gene promoters (Duan et al, 1999;Gillesby et al, 1997;Krishnan et al, 1995;Porter et al, 2001), whereas inhibition of other genes is iDRE-independent . Moreover, the AhR ligand-dependent degradation of ERα may be due to the recently reported E3 ubiquitin ligase activity of the AhR (Ohtake et al, 2007).…”