| Project/Area Number |
18390275
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TANAKA Hirotoshi The University of Tokyo, Institute ofMedical Science, Associate Professor (00171794)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIKAWA Noritada Institute of Medical Science, 医科学研究所, Assistant Professor (70396878)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,620,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2007: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | endocrinology / molecular biology / transcription factor / steroids / gene expression |
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| Research Abstract |
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.
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