Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta (see comments)

FormanBM; TzameliI; ChoiHS; ChenJ; SimhaD; SeolW; EvansRM; MooreDD

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Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta (see comments)

机译：Androstane代谢物与核受体CAR-β结合并使其失活（请参阅评论）

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The orphan receptor CAR-beta binds DNA as a heterodimer with the retinoid-X receptor and activates gene transcription in a constitutive manner. Here we show that, in contrast to the classical nuclear receptors, the constitutive activity of CAR-beta results from a ligand-independent recruitment of transcriptional co-activators. While searching for potential ligands of CAR-beta, we found that the steroids androstanol and androstenol inhibit the constitutive activity of CAR-beta. This effect is stereospecific: only 3alpha-hydroxy, 5alpha-reduced androstanes are active. These androstanes do not interfere with heterodimerization or DNA binding of CAR-beta; instead, they promote co-activator release from the ligand-binding domain. These androstane ligands are examples of naturally occurring inverse agonists that reverse transcriptional activation by nuclear receptors. CAR-beta (constitutive androstane receptor-beta), therefore, defines an unanticipated steroidal signalling pathway that functions in a manner opposite to that of the conventional nuclear receptor pathways.

机译：孤儿受体CAR-beta将DNA作为异二聚体与类视黄醇X受体结合，并以组成型方式激活基因转录。在这里，我们表明，与经典的核受体不同，CAR-β的组成活性是由转录共激活因子的配体独立募集产生的。在寻找CAR-beta的潜在配体时，我们发现类固醇雄甾烷醇和雄甾烯醇会抑制CAR-beta的组成活性。这种作用是立体定向的：只有3α-羟基，5α-还原的雄烷酮具有活性。这些雄甾烷酮不会干扰CAR-beta的异二聚化或DNA结合。相反，它们促进共激活剂从配体结合结构域释放。这些雄甾烷配体是天然存在的反向激动剂的实例，其通过核受体逆转录激活。因此，CAR-β（组成型雄烷受体β）定义了一种意想不到的甾体信号传导途径，其功能与常规核受体途径相反。

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来源
《Nature》 |1998年第6702期|P.612-615|共4页
作者
FormanBM; TzameliI; ChoiHS; ChenJ; SimhaD; SeolW; EvansRM; MooreDD;
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作者单位

The City of Hope National Medical Center, Duarte, California 91010, USA. bforman;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类自然科学总论;
关键词
Androstanes; Androstanols; Receptors; Cytoplasmic and Nuclear; Trans-Activators; 雄甾烷类; 雄甾烷醇类; 受体; 胞质和核; 反式作用因子;

机译：Androstanes;Androstanols;Receptors;Cytoplasmic and Nuclear;Trans-Activators;雄甾烷类;雄甾烷醇类;受体;胞质和核;反式作用因子;

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专利

1. Homology modelling of the nuclear receptors: human oestrogen receptorbeta (hERbeta), the human pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR) ligand binding domains from the human oestrogen receptor al [J] . Jacobs MN, Dickins M, Lewis DF The Journal of Steroid Biochemistry and Molecular Biology . 2003,第2a3期

机译：核受体的同源性建模：人类雌激素受体al（hERbeta），人类孕烷X受体（PXR），Ah受体（AhR）和组成型雄烷受体（CAR）配体结合域
2. A combination of transcriptomics and metabolomics uncovers enhanced bile acid biosynthesis in HepG2 cells expressing CCAAT/enhancer-binding protein β (C/EBPβ), hepatocyte nuclear factor 4α (HNF4α), and constitutive androstane receptor (CAR) [J] . Blazquez M., Carretero A., Ellis J.K., Journal of proteome research . 2013,第6期

机译：转录组学和代谢组学的组合揭示了表达CCAAT /增强子结合蛋白β（C /EBPβ），肝细胞核因子4α（HNF4α）和组成型雄烷受体（CAR）的HepG2细胞中胆汁酸的生物合成增强
3. CCAAT/Enhancer-binding Protein α (C/EBPα) and Hepatocyte Nuclear Factor 4α (HNF4α) Synergistically Cooperate with Constitutive Androstane Receptor to Transactivate the Human Cytochrome P450 2B6 (CYP2B6) Gene [J] . Marta Benet, Agustín Lahoz, Carla Guzmán, The Journal of biological chemistry . 2010,第37期

机译：CCAAT /增强剂结合蛋白α（C /EBPα）和肝细胞核因子4α（HNF4α）与组成型androstane受体协同配合，以转移人细胞色素P450 2b6（CYP2B6）基因
4. Design and synthesis of cyclic peptide antagonists intended to block coactivator binding to steroid nuclear receptors [C] . Anne-Marie Leduc, Kelli S.Bramlett, Thomas P.Burris, the International Peptide Symposium . 2001

机译：旨在阻断与类固醇核受体结合的循环肽拮抗剂的设计和合成
5. Regulation of constitutive androstane receptor and pregnane X receptor. [D] . Ding, Xunshan. 2006

机译：调节组成型雄烷受体和孕烷X受体。
6. CCAAT/Enhancer-binding Protein α (C/EBPα) and Hepatocyte Nuclear Factor 4α (HNF4α) Synergistically Cooperate with Constitutive Androstane Receptor to Transactivate the Human Cytochrome P450 2B6 (CYP2B6) Gene [O] . Marta Benet, Agustín Lahoz, Carla Guzmán, 2010

机译：CCAAT /增强子结合蛋白α（C /EBPα）和肝细胞核因子4α（HNF4α）与组成型雄激素受体协同协同激活人类细胞色素P450 2B6（CYP2B6）基因
7. CCAAT/Enhancer-binding Protein α (C/EBPα) and Hepatocyte Nuclear Factor 4α (HNF4α) Synergistically Cooperate with Constitutive Androstane Receptor to Transactivate the Human Cytochrome P450 2B6 (CYP2B6) Gene: APPLICATION TO THE DEVELOPMENT OF A METABOLICALLY COMPETENT HUMAN HEPATIC CELL MODEL* [O] . Benet, Marta, Lahoz, Agustín, Guzmán, Carla, 2010

机译：CCAAT /增强子结合蛋白α（C /EBPα）和肝细胞核因子4α（HNF4α）与组成型雄甾烷受体协同协同激活人类细胞色素P450 2B6（CYP2B6）基因：在开发代谢型人肝细胞中的应用*
8. Endosulfan-alpha Induces CYP26 and CYP3A4 by Activating the Pregnane X Receptor But Not the Constitutive Androstane Receptor [R] . Casabar, R. C. 2006

机译：硫丹-α通过激活孕烷X受体而不是组成型雄甾烷受体诱导CYp26和CYp3a4

Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta (see comments)

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