Grant-in-Aid for Scientific Research (B).
|Research Institution||Nagoya University|
SEO Hisao Nagoya University., Res.Inst.Environ.Med., Professor, 環境医学研究所, 教授 (40135380)
NAGAYA Takashi Nagoya University., Res.Inst.Environ.Med., Assistant Professor, 環境医学研究所, 助手 (80262913)
KAMBE Fukushi Nagoya University., Res.Inst.Environ.Med., Associate Professor, 環境医学研究所, 助教授 (00211871)
MURATA Yoshihara Nagoya University., Res.Inst.Environ.Med., Professor, 環境医学研究所, 教授 (80174308)
|Project Fiscal Year
1998 – 2000
Completed(Fiscal Year 2000)
|Budget Amount *help
¥5,900,000 (Direct Cost : ¥5,900,000)
Fiscal Year 2000 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Fiscal Year 1999 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 1998 : ¥3,200,000 (Direct Cost : ¥3,200,000)
|Keywords||thyroid hormone receptor / cofactor / dominant negative action / corepressor / coactivator / RXRα / NF-κB / 甲状腺ホルモン受容体 / 共役因子 / ドミナントネガティブ作用 / コリプレッサー / コアクチベーター|
1. DETERMINATION OF CHROMOSOME LOCUS OF HUMAN NUCLEAR COREPRESSOR (hN-CoR)
hN-CoR has been shown to associate with unliganded thyroid hormone receptor and to inhibits the transcription of target genes for thyroid hormone. We localized the locus of hN-CoR on chromosome 17q11.2 by FISH (fluorescent in situ hybridization) and Southern blot analysis using the panel of human and mouse hybrid cell lines. This was the first report on the localization of hN-CoR.
2. STUDIES ON THE ROLE OF N-CoR IN THE PATHOGENESIS OF RESISTANCE TO THYROID HORMONE (RTH)
RTH in most cases is inherited in an autosomal dominant manner. In most of the patients, point mutation were identified in the thyroid hormone receptor (TR) beta gene coding the ligand binding domain. It has been thus speculated that dominant negative action of mutant (TR) on normal TR is the key mechanism for the pathogenesis of RTH.A fact that more than 60 mutations were identified to date, no mutation was reported in the region coding the domai
n which interact with N-CoR.We thus studied whether the disruption of N-CoR binding site in a mutant TR abrogates the dominant negative action of the mutant receptor. It was demonstrated that the disruption eliminates the dominant negative action of the mutant receptor. It is suggested that binding of mutant TR with N-CoR is required for the dominant negative action of the mutant receptors.
3. INTRACELLULAR DEGRADATION OF RETINOID X RECEPTOR (RXR)
It is now accepted that TR exerts its action by heterodimer formation with RXR.It is thus speculated that the metabolism of RXR could modify the action of TR.We demonstrated that RXR is rapidly degraded by a cathepsin-L type protease, a lysozomal enzyme. Furthermore, it was demonstrated that inhibition of this enzyme resulted in an augmented response to thyroid hormone in hepatocyte, demonstrating the metabolism of RXR could influence the action of thyroid hormone.
4. REGULAIION OF RXRa EXPRESSION BY GLUCOCORTICOID IN HEPATOCYTE
Major RXR expressed in the liver has been shown to be RXRα. We demonstrated that glucocorticoid increases the expression of RXRα and enhances thyroid hormone action, suggesting the cross talk between glucocorticoid and thyroid hormone.
5. MODIFICATION OF THYROID HORMONE ACTION BY TNFα
It was demonstrated that nuclear factor kappa-B (NF-κB) activated by inhibits the thyroid hormone dependent activation of 5'-deiodinase gene in liver. This study suggested that mechanism involved in the development of euthyroid sick syndrome caused by an increase in TNFα could be NF-κB dependent inhibition of thyroid hormone action in liver. Less