Pollution Disrupts Endocrine Signaling

Abstract

Dioxins are fat-soluble environmental pollutants that disrupt the endocrine system of humans (see Harper). The aryl hydrocarbon receptor (AhR) binds dioxins; interacts with the AhR nuclear-translocator protein (ARNT) and sex hormone steroid receptors, such as estrogen receptor α (ERα) and androgen receptor (AR); and promotes hormone-independent transcriptional activation. In addition, dioxins also inhibit sex steroid signaling, and Ohtake et al . show that one mechanism for this inhibition is by promoting the proteasome-mediated degradation of the steroid hormone receptors. Exposure of mammary tumor cells (MCF-7) or prostate cancer cells (LNCaP) to various dioxin chemicals decreased the abundance of ERα or AR, respectively. Ubiquitinated ERα was detectable in MCF-7 cells treated with dioxin and in which the proteasome was inhibited. Five dioxin-induced flag-tagged AhR-containing complexes were isolated from HeLa cells, and the "B" complex also contained ubiquitinated components. Complex B, which the authors name CUL4B AhR , contained the ubiquitin ligase components cullin 4B (CUL4B), damaged DNA binding protein (DDB1), and Rbx1; the proteasomal 19 S regulatory particle; ARNT; transducin-β-like 3 (TBL3); and ligand-bound AhR. The complete complex was only formed in the presence of AhR dioxin ligand (in vivo detected by coimmunoprecipitation and in vitro by assembly of isolated constituents). The E3 ubiquitin ligase activity of CUL4B AhR for ERα required dioxin but did not require estrogen. When components of CUL4B AhR were knocked down, dioxin-induced ubiquitination and degradation of ERα were diminished. Injection of dioxin into mice reduced ERα (females) or AR (males) abundance regardless of whether sex steroids were present or absent. Dioxin had no effect in mice deficient for AhR. Thus, AhR appears to trigger the formation of a ligand-induced E3 ubiquitin ligase complex, with AhR serving as the substrate adaptor allowing this complex to target sex steroid receptors. This ligand-dependent E3 ubiquitin ligase is similar to that seen in plants for the auxin receptor, and it will be interesting to see whether there are endogenous ligands for AhR that trigger the formation of this CUL4B AhR E3 ubiquitin ligase. F. Ohtake, A. Baba, I. Takada, M. Okada, K. Iwasaki, H. Miki, S. Takahashi, A. Kouzmenko, K. Nohara, T. Chiba, Y. Fujii-Kuriyama, S. Kato, Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446 , 562-566 (2007). [PubMed] J. W. Harper, A degrading solution to pollution. Nature 446 , 499-500 (2007). [PubMed]