Growth factor midkine : Biological significance, action mechanism, tissue repairing activity and relationship with diseases.

生长因子中期因子：生物学意义、作用机制、组织修复活性以及与疾病的关系。

• 批准号: 08457035
• 负责人: MURAMATSU Takashi
• 金额: $ 4.93万
• 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: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457035/
• 关键词: Midkine; Hepari; NMR; Synaps; Cancer; Neutrophil; Rheumatoid arthritic; Calcium mobilization; サイトカイン; 増殖分化因子; 神経突起伸長; シンデカン; 神経分化; プラスミノーゲン活性化酵素

1.3D structure of midkine was determined NMR.Midkine consists of 2 domains, which have 3 anitipararel beta-sheets. Site-directed mutagenesis of C-domain, which has biological activity, enabled us to identify amino acids required for neurite outgrowth and plasminogen activator enhancing activity. 2.Midkine had neutrophil chemotactic activity, and was found in synovial fluid of rheumatoid arthritis patients, indicating its close correlation with inflammation. Midkine promotes Ca^<2+> mobilization in neutrophils ; by the use of specific inhibitors of signal transduction, tyrosine kinase, P13 kinase and a G-protein-linked receptor were proposed to be involved in the process. 3.Knockout mice lacking midkine gene were produced. They developed normally, but postnatal development of the hippocampus was delayd. 4.Injection of midkine mRNA into Xenopus embryos showed that midkine suppressed mesoderm induction and promoted development of head neurons. Signal transduction downstream from Smad 2 appeared to interact with midkine signaling pathway. 5.Midkine coated beads induced clustering of acetylcholine receptor in muscle cells. Together with midkine expression in synapses, midkine was concluded to be a factor which was secreted from neurons and promoted synaptogenesis. 6.Truncated midkine mRNA devoid of N terminal domain was expressed in a manner specific for tumor. The lymph node metastases showed strong expression of the truncated form. Serum levels of midkine was frequently elevated in cancer patients, especially in those with lung carcinomas.

Midkine的1.3D结构NMR.Midkine由2个域组成，其中有3个Anitipararel Beta片。具有生物学活性的C域的位置定向诱变使我们能够鉴定神经突生长所需的氨基酸和纤溶酶原激活剂增强活性。 2.Midkine具有嗜中性粒细胞趋化活性，在类风湿关节炎患者的滑液中发现，表明其与炎症密切相关。中风促进中性粒细胞中的Ca^<2+>动员。通过使用特定的信号转导抑制剂，酪氨酸激酶，p13激酶和G蛋白链接受体的使用参与了这一过程。 3.产生缺乏Midkine基因的敲除小鼠。他们正常发展，但是海马后产后发育延迟。 4.将中酮mRNA注射到爪蟾胚胎中，表明中心抑制了中胚层诱导并促进了头神经元的发展。 SMAD 2下游的信号转导似乎与Midkine信号通路相互作用。 5.Midkine涂层珠诱导肌肉细胞中乙酰胆碱受体的聚类。与Midkine在突触中的表达一起，Midkine得出结论是从神经元中分泌并促进突触发生的因素。 6.截断的中酮mRNA没有N末端结构域的肿瘤特异性表达。淋巴结转移表现出截短形式的强烈表达。癌症患者，尤其是患有肺癌的患者中，中酮的血清水平经常升高。

项目成果

Takada, T., Toriyama, K., Muramatsu, H., Song, X.-J., Torii, S.and Muramatus, T.: "Midkine, a retinoic acid-inducible heparin-binding cytokine in inflammatory responses : chemotactic activity to neutrophils and association with inflammatory synovitis." J.

Takada, T.、Toriyama, K.、Muramatsu, H.、Song, X.-J.、Torii, S. 和 Muramatus, T.：“Midkine，炎症反应中的一种视黄酸诱导型肝素结合细胞因子：趋化性

Muramatsu,H.ら: "Enzyme-liked immunoassay of midkine and its application in evaluating midkine levels in the developing mouse brain and in sera from patients with hepatocellular carcinoma." J.Biochem.119. 1171-1175 (1996)

Muramatsu, H. 等人：“中期因子的酶样免疫测定及其在评估发育中小鼠大脑和肝细胞癌患者血清中中期因子水平的应用。J.Biochem.1171-1175 (1996)”

Adachi, Y., Matsubara, S., Pedraza, C., Ozawa, M., Tsutsui, J., Takamatsu, H., Noguchi, H., Akiyama, T.and Muramatsu, T.: "Midkine as a novel target gene for the Wilms'tumor suppressor gene (WT1)." Oncogene. 13. 2197-2203 (1996)

Adachi, Y.、Matsubara, S.、Pedraza, C.、Ozawa, M.、Ttsutsui, J.、Takamatsu, H.、Noguchi, H.、Akiyama, T. 和 Muramatsu, T.：“Midkine 作为一部小说

Asai, T., Watanabe, K., Ichihara-Tanaka, K., Kaneda, N., Kojima, S., Iguchi, A., Inagaki, F.and Muramatsu, T.: "Identification of heparin-binding sites in midkine and their role in neurite-promotion." Biochem.Biophys.Res.Common.236. 66-70 (1997)

Asai, T.、Watanabe, K.、Ichihara-Tanaka, K.、Kaneda, N.、Kojima, S.、Iguchi, A.、Inagaki, F. 和 Muramatsu, T.：“鉴定肝素结合位点

Kojima S.ら: "Dimerzation of midkine by transglutaminase and its functional implication" J.Biol.Chem.272. 9410-9416 (1997)

Kojima S.等人：“转谷氨酰胺酶对中期因子的二聚化及其功能意义”J.Biol.Chem.272 (1997)。