The study of the negative regulation of thyrotropin b by thyroid hormone and its receptor
甲状腺激素及其受体对促甲状腺素b负调节作用的研究
基本信息
- 批准号:12671077
- 负责人:
- 金额:$ 1.22万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:2000
- 资助国家:日本
- 起止时间:2000 至 2001
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
It has been postulated that, in the TSH beta promoter, a DMA sequence immediately down stream to the transcription start site may have critical role to mediate the negative regulation driven by thyroid hormone (T3) and its receptor (TR) (Chin, W. W. et al.(1993) Recent. Prog.Horm. Res. 48 : 393-414). We designated this region as Negative Regulatory Element (NRE) and reported that histone deacetylase (HDAC) 2 may be recruited by TR in a T3 dependent manner (Sasaki S, et al. (1999) EMBO J. 18(19):5389-5398). The inspection of NRE sequence predicted the possibility that high mobility group (HMG) proteins may bind NRE and modulate the function of T3 bound TR Using gel shift assay, we confirmed that HMG protein really bind to NRE in T alpha T1 cell which has been established recently as thyrotroph cell line. In addition, we identified a HMG protein, Sox11, using RT-PCR with degenerated primers. The existence of Sox11 was confirmed by the gel sift assay with specific antibody. Furthermore, we established an experimental system in which we can detect the negative regulation of TSH beta gene in monkey kidney cell line, CV 1. The establishment of this experimental system enabled us to analyze the precise mechanisms of the negative regulation of TSH beta gene much easier than before. Using this system, we found that the overexpression of Sox11 eliminated the negative regulation of TSH beta gene by T3 and TR. Surprisingly, however, this system revealed that the negative regulation was maintained even after the destruction of NRE. Further studies suggested the possibility that the transcription factors, Pit1 and GATA2, may not only be critical to activate TSH beta promoter but also the main target of negative regulation by liganded TR.
据推测,在 TSH β 启动子中,紧邻转录起始位点下游的 DMA 序列可能在介导甲状腺激素 (T3) 及其受体 (TR) 驱动的负调节中发挥关键作用(Chin,W. W. 等)等人(1993)最近的研究。 48:393-414)。我们将该区域指定为负调节元件(NRE)并报道组蛋白脱乙酰酶(HDAC)2可以由TR以T3依赖性方式募集(Sasaki S等人(1999)EMBO J.18(19):5389- 5398)。 NRE序列的检查预测了高迁移率基团(HMG)蛋白可能结合NRE并调节T3结合TR的功能的可能性。使用凝胶位移测定,我们证实HMG蛋白确实与已建立的T α T1细胞中的NRE结合最近作为促甲状腺细胞系。此外,我们使用简并引物的 RT-PCR 鉴定了 HMG 蛋白 Sox11。通过特异性抗体的凝胶筛分测定证实了Sox11的存在。此外,我们还建立了一个可以检测猴肾细胞系CV 1中TSH β基因负调控的实验系统。该实验系统的建立使我们能够更加深入地分析TSH β基因负调控的精确机制。比以前更容易。使用该系统,我们发现Sox11的过表达消除了T3和TR对TSH beta基因的负调节。然而,令人惊讶的是,该系统显示,即使在 NRE 被破坏后,负调控仍然得以维持。进一步的研究表明,转录因子 Pit1 和 GATA2 可能不仅对于激活 TSH β 启动子至关重要,而且也是配体 TR 负调控的主要靶标。
项目成果
期刊论文数量(15)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Akio Matsushita: "Very strong correlation between dominant negative activities of mutant thyroid hormone receptors and their binding avidity for corepressor SMRT"J Endocrinol.. 167. 493-503 (2000)
Akio Matsushita:“突变型甲状腺激素受体的显性负性活性与其对辅阻遏物 SMRT 的结合亲合力之间有很强的相关性”J Endocrinol.. 167. 493-503 (2000)
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Kozo Nishiyama: "Differences between the silencing-related properties of the extreme carboxyl-terminal regions of thyroid hormone receptors alpha 1 and beta 1"J Endocrinol.. 167. 219-227 (2000)
Kozo Nishiyama:“甲状腺激素受体 α 1 和 β 1 极端羧基末端区域的沉默相关特性之间的差异”J Endocrinol.. 167. 219-227 (2000)
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松下明生: "TSH受容体不活性化型変異による家族性甲状腺機能低下症(TSH不応症)"日本臨床. 60. 284-290 (2002)
Akio Matsushita:“TSH 受体失活突变引起的家族性甲状腺功能减退症(TSH 难治性)”日本临床。 60. 284-290 (2002)
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佐々木茂和: "転写調節と疾患"診断と治療. 89. 309-315 (2001)
Shigekazu Sasaki:“转录调控与疾病”诊断和治疗。89. 309-315 (2001)。
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Nishiyama K, Kitahara A, Natsume H, Matsushita A, Nakano K, Sasaki S, Genma R, Yamamoto Y, Nakamura H: "Malignant hyperthermia in a patient with Graves' disease during subtotal thyroidectomy"Endocr J. 48-2. 227-32 (2001)
Nishiyama K、Kitahara A、Natsume H、Matsushita A、Nakano K、Sasaki S、Genma R、Yamamoto Y、Nakamura H:“甲状腺次全切除术期间格雷夫斯病患者的恶性高热”Endocr J. 48-2。
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SASAKI Shigekazu其他文献
SASAKI Shigekazu的其他文献
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{{ truncateString('SASAKI Shigekazu', 18)}}的其他基金
The molecular mechanism of the linear-log relation between thyrotropin synthesis and T3
促甲状腺素合成与T3线性对数关系的分子机制
- 批准号:
24590689 - 财政年份:2012
- 资助金额:
$ 1.22万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
相似海外基金
ANALYSIS OF HORMONE BINDING DOMAIN (HBD) OF THYROID HORMONE RECEPTOR (TR)
甲状腺激素受体(TR)的激素结合域(HBD)分析
- 批准号:
6119384 - 财政年份:1999
- 资助金额:
$ 1.22万 - 项目类别:
Functional analysis of thyroid hormone receptor interacting protein
甲状腺激素受体相互作用蛋白的功能分析
- 批准号:
09671045 - 财政年份:1997
- 资助金额:
$ 1.22万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular cloning of thyroid hormone receptor interacting protein using yeast two hybrid system
利用酵母二杂交系统分子克隆甲状腺激素受体相互作用蛋白
- 批准号:
07671126 - 财政年份:1995
- 资助金额:
$ 1.22万 - 项目类别:
Grant-in-Aid for Scientific Research (C)