日本东京大学分子细胞生物学研究所加藤茂名教授领导的研究小组发现，生物体内的二噁英受容体（AhR）能够促进性激素受容体的分解。AhR与其他蛋白质结合，起到分解男女性激素酶的作用。这种蛋白质与其他蛋白质结合后，形成蛋白质复合体，从而获得全新的机能。这不仅是生物学的新发现，而且对乳腺癌、前列腺癌等与性激素分泌有关的癌症的治疗及开发相关预防药物具有重要作用。
AhR可以与二噁英类物质以及废气、烟草中的致癌成分等多种化学物质结合。与其他化学物质结合后AhR会出现多种新的功能，但至今仍未了解其机理。科学家一直从遗传控制的观点对其进行研究。这是科学家首次在动物界发现AhR直接参与对性激素等蛋白质分解的控制。研究论文发表在29日出版的英国《自然》杂志上。
部分英文原文：
Nature 446, 562-566 (29 March 2007) | doi:10.1038/nature05683; Received 13 December 2006; Accepted 16 February 2007
Dioxin receptor is a ligand-dependent E3 ubiquitin ligase
Fumiaki Ohtake1,2, Atsushi Baba2, Ichiro Takada2, Maiko Okada2, Kei Iwasaki1, Hiromi Miki2, Sayuri Takahashi2,3, Alexander Kouzmenko1,2, Keiko Nohara4, Tomoki Chiba5, Yoshiaki Fujii-Kuriyama6,7 & Shigeaki Kato1,2
ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Department of Urology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan
National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan
Graduate School of Life and Environmental Sciences, and,
TARA Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577, Japan
SORST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Correspondence to: Shigeaki Kato1,2 Correspondence and requests for materials should be addressed to S.K. (Email: uskato@mail.ecc.u-tokyo.ac.jp).
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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 regulation1. 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 specificity2, 3, 4. Here we characterize a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which dioxin receptor (AhR)5, 6, 7, 8, 9 is integrated as a component of a novel cullin 4B ubiquitin ligase complex, CUL4BAhR. Complex assembly and ubiquitin ligase activity of CUL4BAhRin vitro and in vivo are dependent on the AhR ligand. In the CUL4BAhR 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.
