2000 Fiscal Year Final Research Report Summary
Mechanisms of Negative Regulation by Thyroid Hormone Receptor and of Crosstalk among Nuclear Hormone Receptors
| Project/Area Number |
11671103
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Research Institute for Production Development |
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Principal Investigator |
TAGAMI Tetsuya Research Institute for Production Development, Laboratory for adult diseases, Researcher, 成人病科学研究室, 研究員 (00301739)
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| Co-Investigator(Kenkyū-buntansha) |
AKAMIZU Takashi Kyoto University Graduate School of Medicine, Department of Medicine and Clinical Science, Assistant Professor, 医学研究科, 講師 (20231813)
MORIYAMA Kenji Research Institute for Production Development, Laboratory for adult diseases, Researcher (00301739)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Thyroid Hormone / Thyroid Hormone Receptor / Thyroid Stimulating Hormone / Transcriptional Regulation / Transcription Factors / Transcriptional cofactors / Histone Acetylation / Nuclear Hormone Receptors |
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| Research Abstract |
Thyroid hormone receptors (TR) function as transcription factors to increase or decrease levels of gene expression. A group of transcriptional cofactors for nuclear hormone receptors, referred to as corepressors (CoR) and coactivators (CoA), has been shown to induce transcriptional silencing and hormone-induced activation, respectively, of genes that contain positive hormone response elements. Transcriptional silencing by CoR involves the recruitment of histone deacetylases (HDAC), whereas ligand-dependent activation is associated with the recruitment of CoA, which possess or recruit histone acetyltransferases (HAT). In a reciprocal manner of T3 dependent activation, negatively regulated genes are stimulated by nuclear receptors in the absence of ligand and are repressed in response to ligand binding to receptors. TR interactions with negatively regulated genes are driven through protein-protein interactions. Negative regulation of the thyroid-stimulating hormone a (TSHα) promoter by T
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R involves a novel mechanism, in which the recruitment of CoR by TR is associated with transcriptional stimulation and histone acetylation and, by the addition of T3, the recruitment of CoA by TR is associated with transcriptional repression and the loss of histone acetylation. We propose that negative regulation of a subset of genes by TR involves the active exchange of HDAC and HAT with intrinsic promoter regulatory elements that normally regulate histone acetylation and transcription. Target sequences were mapped to CRE and downstream of TATA box. To verify these results in vivo, a transgene was created that express HDAC driven by TSHβ promoter. Crosstalk between TR and VDR (vitamin D receptor) was demonstrated, which is caused presumably by sequestrating CoA.The estrogen receptor (ER) can bind weakly with CoR only in the presence of antagonists. The chimeric receptor of ER and CoR was created and it inhibited ER function in breast cancer cells. The CoR binding surface was mapped on the ligand binding domain of TR.Rhei Rhizoma (Rhubarb) stimulated ER- and Bisphenol A inhibited TR- mediated transcription, respectively, as endocrine disrupters. Methimazole and Propylthiouracil suppressed gene transcription mediated by TR.Thus, various chemical compounds may disrupt functions of nuclear hormone receptors by disturbing their utility of CoA and CoR. Less
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