Crosstalk between Ca^<2+>-calcineurin-pathway and thyroid hormone action

Ca^<2>-钙调磷酸酶途径与甲状腺激素作用之间的串扰

• 批准号: 13470217
• 负责人: SEO Hisao
• 金额: $ 5.18万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470217/
• 关键词: ZAKI-4; thyroid hormone; calcineurin; central nervous system; cardoac hypertrophy; rapamycin; mTOR; サイクロスポリンA; カルシウム

We identified a thyroid hormone (T3)-responsive gene, ZAKI-4 in cultured human skin fibroblasts. It belongs to a family of genes that encode proteins containing a conserved motif. The motif binds to and inhibits calcineurin (CN). In this study, we identified three different ZAKI-4 transcripts, α, β1 and β2 in human brain by 5'-and 3'-RACE. The a transcript was identical to that we originally cloned and the other two were novel. The three transcripts are generated by alternative initiation and splicing from a single gene on the short arm of chromosome 6. It is predicted that β1 and β2 encode an identical protein product β, which differs from a in its N-terminus. Both isoforms associate with CN and inhibit its activity through an identical C-terminal region. An examination of expression profile of the three transcripts revealed that a transcript is expressed exclusively in brain, while b transcripts are expressed ubiquitously, most abundantly in brain, heart, skeletal muscle and kidney. … More It was also demonstrated that human skin fibroblasts express both α and β transcripts, raising a question which transcript is upregulated by T3. It was revealed that T3 markedly induced the expression of a isoform but not of β. This T3-mediated increase in the a isoform was associated with a significant decrease in endogenous CN activity. We further explored how T3 regulates the expression of a isoform in human skin fibroblasts. First, effect of calcineurin inhibitor FK506 and its analog rapamycin on T3-mdeiated regulation of ZAKI-4α was studied, because activation of CN was reported to cause an increased expression of a ZAKI-4 family gene, DSCR1. It was demonstrated that T3-mediated increase in ZAKI-4 expression was not inhibited by FK506 but completely abrogated by rapamycin. Since rapamycin is a specific inhibitor of mammalian target of rapamycin (mTOR), we investigated the involvement of mTOR in T3 action. It was demonstrated that T3 activates mTOR kinase through non-genomic action. These data for the first time demonstrated that T3 signaling cascade through mTOR to calcineurin inhibitor ZAKI-4α. Less

我们在培养的人皮肤成纤维细胞中鉴定了甲状腺激素（T3）反应基因ZAKI-4。它属于编码含有保守基序的蛋白质的基因家族。基序结合并抑制钙调磷酸酶（CN）。在本研究中，我们通过5 '-和3'-RACE在人脑中鉴定了三种不同的ZAKI-4转录本，α，β1和β2。转录本与我们最初克隆的完全相同，另外两个是新的。这三个转录本是由6号染色体短臂上的单个基因通过选择性起始和剪接产生的。据预测，β1和β2编码相同的蛋白质产物β，其在其N-末端不同于α。两种亚型均与CN结合并通过相同的C-末端区域抑制其活性。对这三种转录物的表达谱的检查显示，a转录物仅在脑中表达，而B转录物在脑、心脏、骨骼肌和肾中普遍表达，最丰富。 ...更多信息 还证明了人皮肤成纤维细胞表达α和β转录物，提出了T3上调哪种转录物的问题。结果表明，T3能显著诱导α亚型的表达，但对β亚型的表达无明显影响。这种T3介导的α亚型的增加与内源性CN活性的显著降低相关。我们进一步探讨了T3如何调节人皮肤成纤维细胞中同种型的表达。首先，研究了钙调磷酸酶抑制剂FK 506及其类似物雷帕霉素对ZAKI-4α的T3介导的调节的作用，因为据报道CN的活化引起ZAKI-4家族基因DSCR 1的表达增加。结果表明，T3介导的ZAKI-4表达增加不受FK 506抑制，但被雷帕霉素完全消除。由于雷帕霉素是雷帕霉素哺乳动物靶蛋白（mTOR）的特异性抑制剂，我们研究了mTOR参与T3作用。已证明T3通过非基因组作用激活mTOR激酶。这些数据首次证明T3信号通过mTOR级联至钙调磷酸酶抑制剂ZAKI-4α。少

项目成果

P.M.Sadow, E.Koo, H.Seo, Y.Murata, R E.Weiss, et al.: "Thyroid hormone receptor-specific interactions with steroid receptor coactivator-1 in the pituitary."Molecular Endocrinology. 17. 882-894 (2003)

P.M.Sadow、E.Koo、H.Seo、Y.Murata、R E.Weiss 等人：“甲状腺激素受体与垂体中类固醇受体辅激活因子 1 的特异性相互作用。”分子内分泌学。

SIDDIQ Ayesha, MIYAZAKI Takashi, TAKAGISHI Yoshiko, KANOU Yasuhiko, HAYAKAWA Shizu, INQUE Minoru, SEO Hisao, MURATA Yoshiharu: "Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism."Endocrino

SIDDIQ Ayesha、MIYAZAKI Takashi、TAKAGISHI Yoshiko、KANOU Yasuhiko、HAYAKAWA Shizu、INQUE Minoru、SEO Hisao、MURATA Yoshiharu：“大鼠发育过程中大脑中 ZAKI-4 信使核糖核酸的表达以及甲状腺功能减退症的影响。”内分泌

H.Iwata, et al., Y.Murata, H.Seo: "Is bone matrix still important substitute for bone graft surgery-from point of view of heat and MBP activity"Bone. 32(5). S120 (2003)

H.Iwata 等人、Y.Murata、H.Seo：“从热和 MBP 活性的角度来看，骨基质仍然是骨移植手术的重要替代品吗”Bone.

Shibata A, et al., Seo H: "Inhibition of NF-kappaB activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells"Breast Cancer Research & Treatment. 73(3). 237-243 (2002)

Shibata A 等人和 Seo H：“抑制 NF-kappaB 活性可降低 MDA-MB-231 乳腺癌细胞中 VEGF mRNA 的表达”乳腺癌研究

TAKEUCHI Yoko, MURATA Yoshiharu, SADOW Peter, HAYASHI Yoshitaka, SEO Hisao, XU.Jianming, OMALLEY B.W., WEISS Roy E., REFETOFF Samuel: "Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of T(3)-regulated transcription

TAKEUCHI Yoko, MURATA Yoshiharu, SADOW Peter, HAYASHI Yoshitaka, SEO Hisao, XU.Jianming, OMALLEY B.W., WEISS Roy E., REFETOFF Samuel：“类固醇受体辅激活因子 1 缺乏导致 T(3) 调节的调节发生变化