Clarification of molecular mechanism for regulation of ghucocorticoid receptor function

阐明糖皮质激素受体功能调节的分子机制

• 批准号: 18390275
• 负责人: TANAKA Hirotoshi
• 金额: $ 11.28万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390275/
• 关键词: endocrinology; molecular biology; transcription factor; steroids; gene expression

The phenylpyrazolo glucocorticoid cortivazol (CVZ) is a unique synthetic glucocorticoid agonist with complex binding properties. We demonstrated that CVZ selectively binds to the glucocorticoid receptor (GR) and the functional interaction of CVZ with the GR LBD is different from that of canonical glucocorticoids. Structural docking analysis revealed that CVZ can be accommodated in the ligand binding pocket of the GR by reorientation of several amino acid side chains but without major alterations in the active conformation of the LBD. These results support a model where ligand-dependent conformational changes in the LBD play a role in GR-mediated gene regulation via modular interaction with the DBD and activation function-1. Moreover, transcriptome profile analyses revealed that the different molecular structures have differential effects on individual target genes. We previously reported that HEXIM1 directly associates with GR to suppress glucocorticoid-inducible gene activation. We here revealed that the hinge region of GR is essential for its interaction with HEXIM1, and that oxosteroid receptors including GR show sequence homology in their hinge region and interact with HEXIM1, whereas the other members of nuclear receptors do not. It is concluded that HEXIM1 may act as a gene-selective transcriptional regulator via direct interaction with certain transcriptional regulators including GR and contribute to fine-tuning of, for example, glucocorticoid-mediated biological responses. In this line, we revealed that not P-TEFb suppressing activity but direct interaction with GR plays a major role in suppression of promoter recruitment of the receptor to the promoter regions of atplal and scnnla. Collectively, we may conclude that HEXIM1 may participate in tissue- and gene-selective determination of glucocorticoid sensitivity via direct interaction with GR at least in certain gene set including atplal and scnnla.

苯基吡唑唑糖皮质激素皮质唑（CVZ）是一种独特的合成糖皮质激动剂，具有复杂的结合特性。我们证明了CVZ选择性结合与糖皮质激素受体（GR），并且CVZ与GR LBD的功能相互作用与规范性糖皮质激素的功能相互作用不同。结构对接分析表明，CVZ可以通过重新定位几个氨基酸侧链来容纳在GR的配体结合袋中，但在LBD的主动构象中没有重大改变。这些结果支持一个模型，其中LBD中依赖配体的构象变化通过与DBD和激活函数1的模块化相互作用在GR介导的基因调节中起作用。此外，转录组谱分析表明，不同的分子结构对单个靶基因具有不同的影响。我们先前报道了Hexim1与GR直接关联以抑制糖皮质激素诱导的基因活化。我们在这里透露，GR的铰链区域对于它与Hexim1的相互作用至关重要，而包括GR（GR）在其铰链区域中显示序列同源性并与Hexim1相互作用，而核受体的其他成员则没有。得出的结论是，Hexim1可以通过与某些转录调节剂的直接相互作用（包括GR）直接相互作用充当基因选择性转录调节剂，并有助于糖皮质激素介导的生物学反应进行微调。在这一行中，我们透露，不是P-TEFB抑制活性，而是与GR的直接相互作用在抑制受体募集到Atplal和Scnnla启动子区域的启动子募集中起着重要作用。总的来说，我们可以得出结论，Hexim1可以通过与GR的直接相互作用至少在某些基因组中直接相互作用来参与组织和基因选择性测定糖皮质激素敏感性，包括ATPLAL和SCNNLA。

项目成果

Glucocorticoid receptor and biological systems

糖皮质激素受体和生物系统

• 发表时间: 2008
• 作者: Muchir A;Pavlidis P;Bonne G;Hayashi YK;Worman HJ.;田中廣壽;Hirotoshi Tanaka
• 通讯作者: Hirotoshi Tanaka

Menage-a-trois 1 is critical for the transcriptional function of PPARgamma coactivator 1

Menage-a-trois 1 对于 PPARgamma 共激活因子 1 的转录功能至关重要

• 发表时间: 2007
• 期刊: Cell Metab 5
• 作者: Sano;M.;Izumi;Y.;Helenius;K.;Asakura;M.;Rossi;D.J.;Xie;M.;Taffet;G.;Hu;L.;Pautler;R.G.;Wilson;C.R.;Boudina;S.;Abel;E.D.;Taegtmeyer;H.;Scaglia;F.;Graham;B.H.;Kralli;A. Shimizu;N.;Tanaka;H.;Makela;T. P.;Schneider;M.D
• 通讯作者: M.D

Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1

• DOI: 10.1074/jbc.m609157200
• 发表时间: 2007-03-30
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Ohnuma, Kei;Uchiyama, Masahiko;Morimoto, Chikao
• 通讯作者: Morimoto, Chikao

Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of PGC-lalpha

PGC-lalpha 的蛋白质稳定性、亚核区室化和共激活剂功能的分子内控制

• 发表时间: 2007
• 期刊: J. Biol Chem 282
• 作者: Shalaby S;Hayashi YK;Nonaka I;Noguchi S;Nishino I;Motoaki Sano
• 通讯作者: Motoaki Sano

グルココルチコイドレセプターと生体機能調節

糖皮质激素受体与生物功能调节

• 发表时间: 2008
• 作者: Muchir A;Pavlidis P;Bonne G;Hayashi YK;Worman HJ.;田中廣壽
• 通讯作者: 田中廣壽