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Vascular regulation by kringles of HGF and molecular cloning of a novel kringle-containing protein

HGF 的三环对血管的调节以及一种新型三环蛋白的分子克隆

基本信息

批准号：
11680631
负责人：
MATSUMOTO Kunio
金额：
$ 2.37万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680631/
关键词：
HGF kringle domain NK4 angiogenesis tumor angiogenesis Kremen metastasis pancreatic cancer 肝細胞増殖因子 HGT 癌治療クリングル制癌剤

项目摘要

Various proteins containing kringle domains play diverse roles in tissue regeneration, blood coagulation/fibrinolysis, neural development, and blood vessel regulation. Identification of a novel kringle-containing molecule is likely to lead to further understanding of blood vessel regulation, including angiogenesis and anti-angiogenesis. In the present study, to study regulatory mechanisms by which kringle domains exhibit angio-regulatory functions, we analyzed angiostatic action of NK4, previously identified as HGF-antagonist. Likewise, we succeeded in molecular cloning of a novel kringle-containg molecule, Kremen.1) NK4 as angiogenesis inhibitor : NK4, a four kringles-cpontaining HGF-antagonist, inhibited proliferation and migration of vascular endothelial cells in culture. Likewise, NK4 inhibited angiogenesis in CAM and cornea assays in vivo. Together with a previously characterized biological action of NK4 as HGF-antagonist, therapeutic potential of NK4 for treatment of metastatic c … More ancers were tested. NK4 administered into mice potently suppressed metastasis, tumor angiogenesis, and tumor growth of cancers, including lung, breast, and pancreatic cancers. NK4 will become a potent anti-cancer agent, targeting malignant behavior of cancer.2) Using a newly established cloning strategy for kringle-containg proteins, 'Kringle-SAGE', we cloned cDNA for Kremen. Kremen is composed of 473 amino acids and is type-I transmembrane protein. Kremen contains unique domains, kringle domain and CUB domain in its extracellular region, while it has no specific conserved functional motif in its intracellular region. Kremen mRNA is expressed in diverse tissues, while it is up-regulated during muscular and neural differentiation. Kringle domain of Although Kremen may have some roles in vascular regulation and differentiation of muscular and neural cells, its roles remain to be further addressed. A newly established method for comprehensive cloning of kringle-proteins, Kringle-SAGE is powerful in molecular cloning of kringle proteins. Less

含有Kringle结构域的各种蛋白质在组织再生、血液凝固/纤维蛋白溶解、神经发育和血管调节中发挥不同的作用。鉴定一种新的含Kringle的分子可能会导致对血管调节的进一步理解，包括血管生成和抗血管生成。在本研究中，为了研究Kringle结构域表现出血管调节功能的调节机制，我们分析了NK 4的血管抑制作用，NK 4以前被鉴定为HGF拮抗剂。同样，我们成功地克隆了一种新的含Kringle的分子，Kremen。1）NK 4作为血管生成抑制剂：NK 4，一种含四个Kringle的HGF拮抗剂，抑制培养的血管内皮细胞的增殖和迁移。同样，在CAM和角膜体内试验中，NK 4抑制血管生成。与先前表征的NK 4作为HGF拮抗剂的生物学作用一起，NK 4用于治疗转移性肝癌的治疗潜力被证实是潜在的。 ...更多信息检查了癌症。施用到小鼠中的NK 4有效地抑制癌症（包括肺癌、乳腺癌和胰腺癌）的转移、肿瘤血管生成和肿瘤生长。NK 4将成为一种有效的抗癌药物，靶向肿瘤的恶性行为。2）利用新建立的含Kringle蛋白的克隆策略"Kringle-SAGE“，我们克隆了Kremen的cDNA。Kremen由473个氨基酸组成，是I型跨膜蛋白。Kremen在胞外区含有独特的结构域、kringle结构域和CUB结构域，而在胞内区没有特异的保守功能基序。Kremen mRNA在不同组织中表达，而在肌肉和神经分化过程中上调。Kringle结构域可能在血管调节、肌肉和神经细胞分化中发挥一定作用，但其作用仍有待进一步研究。Kringle-SAGE是一种新建立的Kringle蛋白质分子克隆方法。少