日本東京大學(xué)分子細(xì)胞生物學(xué)研究所加藤茂名教授領(lǐng)導(dǎo)的研究小組發(fā)現(xiàn),，生物體內(nèi)的二噁英受容體（AhR）能夠促進(jìn)性激素受容體的分解,。AhR與其他蛋白質(zhì)結(jié)合，起到分解男女性激素酶的作用,。這種蛋白質(zhì)與其他蛋白質(zhì)結(jié)合后,，形成蛋白質(zhì)復(fù)合體，從而獲得全新的機(jī)能,。這不僅是生物學(xué)的新發(fā)現(xiàn),，而且對(duì)乳腺癌、前列腺癌等與性激素分泌有關(guān)的癌癥的治療及開發(fā)相關(guān)預(yù)防藥物具有重要作用,。
AhR可以與二噁英類物質(zhì)以及廢氣,、煙草中的致癌成分等多種化學(xué)物質(zhì)結(jié)合。與其他化學(xué)物質(zhì)結(jié)合后AhR會(huì)出現(xiàn)多種新的功能,，但至今仍未了解其機(jī)理,。科學(xué)家一直從遺傳控制的觀點(diǎn)對(duì)其進(jìn)行研究,。這是科學(xué)家首次在動(dòng)物界發(fā)現(xiàn)AhR直接參與對(duì)性激素等蛋白質(zhì)分解的控制,。研究論文發(fā)表在29日出版的英國(guó)《自然》雜志上。
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: [email protected]).
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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.
