REGULATION OF THYROID FUNCTION BY TRANSCRIPTION FACTOR NF-kappaB

转录因子 NF-κB 对甲状腺功能的调节

• 批准号: 07457222
• 负责人: SEO Hisao
• 金额: $ 3.46万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457222/
• 关键词: Nuclear factor kappa B (NFkB); Thyroid Cancer; Superoxide Dismutase; Glutathione Peroxidase; Thyrotropin (TSH); Tumor Necrosis Factor (YNF); NFκB(Nuclear factor kappa B); 腫瘍壊死因子(Tumor necrotic factor=TNF); TSH; NF-κB; FRTL-5細胞; Mn-SOD; ゲルシフト

1. ROLE OF ROI-SCAVENGING SYSTEM IN THYROID CANCERIt has been shown that monocytes infiltrating cancer cells secret cytokines with cytocidal effect. The effect of cytokine is exerted by the production of reactive oxygen intermediates (ROI). It is thus possible that ROI-scavenging system in the cancer cell confer the ability to antagonize the cytotoxic effect of the cytokines. In this study, we investigated the expression of mRNAs coding for ROI-scavengers such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and correlated their expression with indices for malignancies such as lymphatic metastasis. It was revealed that the expression of manganese-SOD mRNA was significantly higher in papillary thyroid cancer cells with lymphatic metastasis. There was no correlation with the expression of Copper-Zinc SOD and GPX with lymphatic metastasis. No correlation was found with local invasion and the expression of these mRNAs. It is thus suggested that the higher expression of manganese … More -SOD in papillary cancer cells renders them to survive after lymphatic metastasis.2. STUDIES ON THE MECHANISM FOR THE ACTIVATION OF NF-kB IN FRTL-5 RAT THYROID CELLSIt is well known that cytokines such as TNF-a and interleukin-6 play important role for the development of autoimmune thyroid disorder. Also known is the fact that high levels of thyroid stimulating hormone aggravate the disorder. Since the effect of cytokines such as TNF-a is mediated through tranlocation of Nuclear factor k B (NF-kB) into the nucleus (activation), it is studied whether TSH modifies the activation of NF-kB by TNF-a. When FRTL-5 cells were not stimulated by TNF-a, no activation of NF-kB was observed. When the cells were stimulated with TNF-a alone, only p50-homodimer was observed in the nuclei. Combined treatment of the cells with TSH and TNF-a resulted in the appearance of p50-p65 heterodimer in the nuclei. Although p50, a subfamily of NF-kB,has DNA-binding activity, it lacks activation domain. Therefore, p50 homodimer is transcriptionally inactive. On the other hand, p65 has both DNA-binding and activation domains. Our finding that induction of p50-p65 heterodimer by TNF-a requires TSH indicates that suppression of TSH in may improve autoimmune thyroid disorder.3. TSH-MEDIATED REGULATION OF THIOREDOXIN (TRX) AND REDOX FACTOR (Ref-1)It has been recently shown that activation of NF-kB requires reduction by the enzymes such as TRX and Ref-1. As mentioned above, TSH modulates the activation of NF-kB TNF-a, it is investigated whether TSH regulates the expression of TRX and Ref-1 in FRTL-5 cells. It was demonstrated that TSH increases the expression of both TRX and Ref-1. Less

1. 一氧化氮清除系统在甲状腺癌中的作用研究表明，浸润癌细胞的单核细胞分泌具有杀细胞作用的细胞因子。细胞因子的作用是通过产生活性氧中间体（ROI）来发挥的。因此，癌细胞中的roi清除系统可能具有对抗细胞因子的细胞毒性作用的能力。在这项研究中，我们研究了编码roi清除剂如超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPX）的mrna的表达，并将其表达与淋巴转移等恶性肿瘤指标进行了关联。结果显示，锰- sod mRNA在甲状腺乳头状癌淋巴转移细胞中表达显著升高。铜锌超氧化物歧化酶和GPX的表达与淋巴转移无关。没有发现与局部侵袭和这些mrna的表达相关。因此，提示乳头状癌细胞中锰的高表达和-SOD的高表达使其在淋巴转移后存活。FRTL-5大鼠甲状腺细胞NF-kB活化机制的研究众所周知，TNF-a和白细胞介素-6等细胞因子在自身免疫性甲状腺疾病的发生发展中起着重要作用。众所周知，高水平的促甲状腺激素会加重这种疾病。由于细胞因子如TNF-a的作用是通过核因子k - B （NF-kB）易位进入细胞核（活化）介导的，因此研究TSH是否通过TNF-a修饰NF-kB的活化。当FRTL-5细胞不受TNF-a刺激时，未观察到NF-kB的活化。单独用TNF-a刺激细胞时，细胞核中只观察到p50同型二聚体。用TSH和TNF-a联合处理细胞导致细胞核中出现p50-p65异源二聚体。NF-kB亚家族p50虽然具有dna结合活性，但缺乏激活结构域。因此，p50二聚体在转录上是无活性的。另一方面，p65同时具有dna结合域和激活域。我们发现TNF-a诱导p50-p65异源二聚体需要TSH，这表明抑制TSH可能改善自身免疫性甲状腺疾病。tsh介导的硫氧还蛋白（TRX）和氧化还原因子（Ref-1）的调控研究表明，NF-kB的激活需要TRX和Ref-1等酶的还原。如前所述，TSH调节NF-kB TNF-a的激活，研究TSH是否调节FRTL-5细胞中TRX和Ref-1的表达。结果表明，TSH可增加TRX和Ref-1的表达。少

项目成果

Nagaya T,Fujieda M,Ohmori S,Seo H: "Molecular cloning of a thyroid hormone receptor interacting protein." Environmental Medicine. 40(1)(in press). (1996)

Nagaya T，Fujieda M，Ohmori S，Seo H：“甲状腺激素受体相互作用蛋白的分子克隆。”

Kambe F,他: "Redox regulation of thyroid-transcription factors,Pax-8 and TTF-1,is involved in their increased DNA-binding activities by thyrotropin in rat thyroid FRTL-5 cells." Molecular Endocrinology. 10. 801-812 (1996)

Kambe F 等人：“甲状腺转录因子 Pax-8 和 TTF-1 的氧化还原调节与促甲状腺素在大鼠甲状腺 FRTL-5 细胞中增加 DNA 结合活性有关。”10. 801。 -812 (1996)

神部 福司他: "培養甲状腺細胞株FRTL-5における転写調節因子NF-kBのDNA結合能のホルモンによる変動" 名古屋大学環境医学研究所年報. 47(印刷中). (1996)

Fukuji Kambe 等人：“培养的甲状腺细胞系 FRTL-5 中转录调节因子 NF-kB 的 DNA 结合能力的激素诱导变化”名古屋大学环境医学研究所年度报告 47（正在出版）。 (1996)

Kambe F,Nomura Y,Okamoto T,Seo H.: "Redox regulation of thyroid-transcription factors, Pax-8 and TTF-1, is involved in their increased DNA-binding activities by thyrotropin in rat thyroid FRTL-5 cells." Molecular Endocrinology. 10. 801-812 (1996)

Kambe F、Nomura Y、Okamoto T、Seo H.：“甲状腺转录因子 Pax-8 和 TTF-1 的氧化还原调节与大鼠甲状腺 FRTL-5 细胞中促甲状腺素增加的 DNA 结合活性有关。”

Kambe F,Miyazaki T and Seo H: "Differential induction of fos and jun family genes by thyrotropin in rat thyroid FRTL-5 cells." Thyroid. 6(2). 123-128 (1996)

Kambe F、Miyazaki T 和 Seo H：“促甲状腺素在大鼠甲状腺 FRTL-5 细胞中对 fos 和 jun 家族基因的差异诱导”。