Modification of thyroid hormone action and molecular cloning of cDNA encoding cellular transporter of thyroid hormones.

甲状腺激素作用的修饰和编码甲状腺激素细胞转运蛋白的 cDNA 的分子克隆。

• 批准号: 06671015
• 负责人: ICHIKAWA Kazuo
• 金额: $ 1.54万
• 依托单位: Shinshu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671015/
• 关键词: Thryoid hormone; Cellular T3 transport; Nuclear T3 uptake; Sodium butyrate; Cell cycle; Nuclear T3 receptor; Cell proliferation; Cytokines; Sick euthyroid syndrome; GH_3細胞; アフリカツメガエル卵母細胞; T3 carrier protein; 発現クローニング

1). During cell growth cycle of cultured rat hepatoma cells (dRLH-84) , cellular and nuclear uptake of triiodothyronine (T3) was manimal in early G1 phase, was gradually incresed toward late G1 phase. Levels of the nuclear T3 receptor also increased in late G1 phase. T3 promoted the proliferation of dRLH-84 cells through shortening of late G1 phase in this cell line. These data indicate that cells are sensitive to T3 in late G1 phase. On the other hand, cellular and nuclear thyroxine (T4) uptake was not altered during cell cycle, indicating the difference in the cellular transport mechanism between T3 and T4. Such a difference was also supported by the differences between T3 and T4 in increases of cellular and nuclear uptake after sodium butyrate treatment. 2) The thyromimetic compound, SK&F L-94901 (SKF) , exerts its activity on liver but not on heart or pituitary gland and may be useful for medical treatment of hyperlipidemia without extrahepatic adverse effects. We proved that SKF exerts liver-specific thyromimetic activity at the level of cellular transoprt of hormones, but not at the level of nuclear receptor. This suggests that cellular transport of thyroid hormone deffers among organs. 3). Recent studies suggest the involvement of cytokines (IL-1 beta, IL-6, TNF alpha) in pathogenesis of sick euthyroid syndrome (SES) . We found that alteration of thyroid hormone uptake and hormone action by cytokines, may explain decrese in basal and TRH-induced serum TSH levels despite low serum T3 levels in SES.The data also suggest that cytokines modify thyroid hormone action. 4) By means of Xenopus oocyte expression system, we proved that mRNA encoding cellular transporter of thyroid hormone exists in cultured rat pituitary cells (GH3 cells).

1).在培养的大鼠肝癌细胞（dRLH-84）的细胞生长周期中，细胞和细胞核对三碘甲状腺原氨酸（T3）的摄取在G1期早期为动物，在G1期晚期逐渐增加。核T3受体水平也在G1期晚期升高。T3通过缩短dRLH-84细胞系G1期晚期促进细胞增殖。这些数据表明细胞在G1期晚期对T3敏感。另一方面，细胞和核甲状腺素（T4）摄取在细胞周期中没有改变，这表明T3和T4在细胞运输机制上存在差异。丁酸钠处理后T3和T4细胞和细胞核摄取增加的差异也支持了这种差异。2)拟甲状腺化合物SK&F L-94901 （SKF）对肝脏有活性，但对心脏或脑垂体没有作用，可能对高脂血症的医学治疗有用，且无肝外不良反应。我们证明SKF在激素的细胞转运水平上发挥肝脏特异性的拟甲状腺活性，而不是在核受体水平上。这表明甲状腺激素的细胞转运在器官之间存在差异。3）. 近年来的研究表明，细胞因子（IL-1 β、IL-6、TNF α）参与了病态甲状腺功能亢进综合征（SES）的发病过程。我们发现甲状腺激素摄取的改变和细胞因子对激素的作用可能解释了尽管SES的血清T3水平较低，但基础和trh诱导的血清TSH水平降低。数据还表明，细胞因子可以改变甲状腺激素的作用。4)利用爪蟾卵母细胞表达系统，证实了在培养的大鼠垂体细胞（GH3细胞）中存在编码甲状腺激素细胞转运体的mRNA。

项目成果

Akira Sato, Toru Aizawa, Yoichi Koizumi, Ichiro Komiya, Kazuo Ichikawa, Takashi Yamada: "Ten-year follow-up study of thyroid function in euthyroid patients with simple goiter of Hashimoto's thyroiditis" Internal Medicine. 34. (1995)

Akira Sato、Toru Aizawa、Yoichi Koizumi、Ichiro Komiya、Kazuo Ichikawa、Takashi Yamada：“桥本甲状腺炎单纯性甲状腺肿患者甲状腺功能正常的十年随访研究”内科。

T.Takeda: "Response of hepatic proteins to 3.5.3′-triiodo-L-thyronine in diabetic rats." Journal of Endocrinology. 143. 55-63 (1994)

T.Takeda：“糖尿病大鼠肝蛋白对 3.5.3′-三碘-L-甲状腺氨酸的反应。”内分泌学杂志 143. 55-63 (1994)

Akihiro Sakurai, Satoru Suzuki, Miyuki Katai, Takahide Miyamoto, Hiroaki Kobayashi, Kouji Nakajima, Kazuo Ichikawa Leslie J DeGroot, Kiyoshi Hashizume: "Transcriptional regulation of human thyroid hormone receptor beta1 gene expression : effect of human r

Akihiro Sakurai、Satoru Suzuki、Miyuki Katai、Takahide Miyamoto、Hiroaki Kobayashi、Kouji Nakajima、Kazuo Ichikawa Leslie J DeGroot、Kiyoshi Hashizume：“人类甲状腺激素受体 beta1 基因表达的转录调控：人类 r 的影响

Kesami Minemura, Takeshi Nagasawa, Masahiro Hara, Kazuo Ichikawa, Kiyoshi Hashizume: Proliferation of cultured rat hepatoma cells mediated through nuclear thyroid hormone receptor.Proceedings of Japanese Clinical Metabolism in press for 1996,

Kesami Minemura、Takeshi Nagasawa、Masahiro Hara、Kazuo Ichikawa、Kiyoshi Hashizume：通过核甲状腺激素受体介导的培养大鼠肝癌细胞的增殖。《日本临床代谢杂志》1996 年出版，

Masahiro Hara, Takeshi Nagasawa, Kesami Minemura, Kazuo Ichikawa, Kiyoshi Hashizume: Alteration of thyroid hormone action in rat hepatoma cells during cell cycle. Proceedings of Japanese Clinical Metabolism in press for 1996,

Masahiro Hara、Takeshi Nagasawa、Kesami Minemura、Kazuo Ichikawa、Kiyoshi Hashizume：细胞周期期间大鼠肝癌细胞中甲状腺激素作用的改变。