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

1.确定了Midkine的三维结构，Midkine由2个结构域组成，分别含有3个抗帕拉雷β-折叠。对具有生物活性的C结构域进行定点突变，使我们能够确定轴突生长和纤溶酶原激活剂增强活性所需的氨基酸。2.中期因子具有中性粒细胞趋化活性，并在类风湿关节炎患者滑液中发现，提示其与炎症密切相关。中期因子通过信号转导的特异性抑制剂促进中性粒细胞的钙动员，酪氨酸激酶、P13激酶和G蛋白连接的受体被认为参与了这一过程。3.建立了缺乏Midkine基因的基因敲除小鼠。它们发育正常，但海马体的出生后发育延迟。4.非洲爪哇胚胎注射中期因子后发现，中期因子抑制了中胚层的诱导，促进了头部神经元的发育。Smad2下游的信号转导通路可能与中期因子信号通路相互作用。5.中期因子包被的微球诱导肌细胞中乙酰胆碱受体的聚集。与突触中中期因子的表达一起，中期因子被认为是一个由神经元分泌并促进突触形成的因子。6.缺失N末端结构域的截短型Midkine基因以肿瘤特异性方式表达。淋巴结转移灶呈截断型强阳性表达。癌症患者血清中期因子水平经常升高，尤其是肺癌患者。

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.