Studies on the role of the JAK-STAT pathway in the regulation of growth and the function of insulin-secreting cells.

JAK-STAT 通路在胰岛素分泌细胞生长和功能调节中的作用研究。

• 批准号: 09671032
• 负责人: SEKINE Nobuo
• 金额: $ 1.86万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671032/
• 关键词: diabetes mellitus; insulin-secreting cells; cytokine; growth hormone; JAK-STAT pathway; tyrosine phosphorylation; transcription factor; nitric oxide(NO); DNA結合蛋白

Recent investigations have established the JAK-STAT pathway as major signalling events for various cytokines and growth factors. The aim of this study was to investigate the role of the JAK-STAT pathway in the regulation of growth and the function of insulin-secreting cells using a rat insulinoma cell line INS-1.1. (1) Growth hormone (GH) and prolactin (PRL), both of which stimulate growth and insulin biosynthesis of insulin-secreting cells, activated JAK2 tyrosine kinase followed by phosphorylation and DNA-binding of STAT5. (2) In contrast to previous reports in other cell types, GH failed to activate mitogen-activated protein (MAP) kinase in INS-I cells. This could be explained by limited expression of epidermal growth factor (EGF) receptor, which was found to be phosphorylated by GH, in this cell line.2. (1) Interferon (IFN)-gamma inhibited nutrient-induced insulin secretion mainly through the inhibition of mitochondrial metabolism in INS-I cells. Moreover, IFN-gamma in combination with tumor necrosis factor (TNF)-alpha elicited cytotoxic effects in INS-I cells. This was observed in parallel with expression of the inducible isoform of nitric oxide (NO) synthase (iNOS), thereby producing NO, which may cause cytotoxicity. (2) IFN-gamma promoted tyrosine phosphorylation and DNA-binding of STAT 1, whereas TNF-alpha activated NE-kappaB, which was found to be further activated by IFN-gamma. The activation of STAT1 by IEN-gamma may be involved, directly or indirectly via the activation of IRF-1, in the expression of NO.In addition, the synergistic activation of NE-kappaB by the two cytokines might be an essential event for the iNOS induction.Taken together, it is suggested that the activation of JAK2 and STAT5 by GH or PRL is implicated in the stimulation, whereas that of STAT1 by IFN-gamma may lead to the inhibition, of growth and the function of insulin-secreting cells.

最近的研究已经确定JAK-STAT通路是各种细胞因子和生长因子的主要信号事件。本研究的目的是利用大鼠胰岛素瘤细胞系INS-1.1研究JAK-STAT通路在调节胰岛素分泌细胞生长和功能中的作用。(1)促胰岛素分泌细胞生长和胰岛素生物合成的生长激素（Growth hormone， GH）和催乳素（prolactin， PRL）激活JAK2酪氨酸激酶，STAT5磷酸化并与dna结合。(2)与之前报道的其他细胞类型不同，生长激素在INS-I细胞中未能激活丝裂原活化蛋白激酶（MAP）。这可以解释为表皮生长因子（EGF）受体在该细胞系中的表达有限，该受体被GH磷酸化。(1)干扰素(IFN)- γ主要通过抑制INS-I细胞的线粒体代谢抑制营养诱导的胰岛素分泌。此外，ifn - γ与肿瘤坏死因子(TNF)- α联合在INS-I细胞中引起细胞毒性作用。与此同时，一氧化氮（NO）合成酶（iNOS）的诱导异构体表达，从而产生可能引起细胞毒性的NO。(2) ifn - γ促进酪氨酸磷酸化和STAT 1的dna结合，而tnf - α激活NE-kappaB，发现ifn - γ进一步激活NE-kappaB。ien - γ激活STAT1可能直接或间接通过激活IRF-1参与NO的表达。此外，两种细胞因子对NE-kappaB的协同激活可能是诱导iNOS的重要事件。综上所述，这表明GH或PRL对JAK2和STAT5的激活与刺激有关，而ifn - γ对STAT1的激活可能导致胰岛素分泌细胞的生长和功能的抑制。

项目成果

Yamauchi T et al.: "Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone." Nature. 390. 91-96 (1997)

Yamauchi T 等人：“激酶 Jak2 对 EGF 受体的酪氨酸磷酸化是由生长激素诱导的。”

Yamauchi T et al.: "Tyrosine phosphorylation of the EGF recuptor by the kinese Jak2 is induced by growth hormone." Nature. 390. 91-96 (1997)

Yamauchi T 等人：“生长激素诱导了激酶 Jak2 对 EGF 受体的酪氨酸磷酸化。”

関根信夫: "インスリン分泌不全" 医学のあゆみ 内分泌代謝疾患 state of ares. 98-100 (1997)

Nobuo Sekine：“胰岛素分泌不足”医学史内分泌和代谢疾病状态98-100（1997）。

Sekine N et al.: "GH signalling in pancreatic・β・cells." Endocrine Journal. (in press). (1998)

Sekine N 等人：“胰腺·β·细胞中的 GH 信号传导”（内分泌杂志）（1998 年）。

Yamauchi T et al.: "Growth hormone-induced tyrosine phosphorylation of EGF receptor as an essential element leading to MAP kinase activation ond gene expression." Endocvine Journal. 45. S27-S31 (1998)

Yamauchi T 等人：“生长激素诱导的 EGF 受体酪氨酸磷酸化是导致 MAP 激酶激活和基因表达的重要因素。”