p22 is a novel plasminogen fragment with antiangiogenic activity
p22 is a novel plasminogen fragment with antiangiogenic activity
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DOI：
10.1021/bi0113420
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发表时间：
2001-11-06
期刊：
影响因子：
2.9
通讯作者：
Waisman, DM
中科院分区：
文献类型：
--
作者：
Kwon, M;Yoon, CS;Waisman, DM
肿瘤或肿瘤相关细胞将循环的纤溶酶原切割成三到四个含kringle的抗血管生成片段，统称为血管抑制素。血管抑制素通过阻止对肿瘤血管化至关重要的内皮细胞的生长来阻止肿瘤的生长和转移。在这里，我们发现癌症和正常细胞将纤溶酶原转化为一个新的22 kDa片段（p22）。在无细胞系统中产生这种纤溶酶原片段可以表征蛋白质的结构和活性。p22由纤溶酶原氨基酸残基78-180组成，因此包含了第一个纤溶酶原kringle（残基84-162）以及附加的N端和c端残基。圆二色性和本征荧光光谱分析确定了p22和重组纤溶酶原kringle 1 （rK1）之间的结构差异，因此表明p22中kringle 1具有独特的构象。p22对毛细血管内皮细胞的增殖有选择性抑制作用，但对其他细胞系的细胞没有抑制作用。此外，p22还能抑制鸡绒毛膜尿囊膜（CAMs）的血管生长。此外，低剂量p22在体内抑制小鼠Lewis肺癌（LLC）转移灶的生长。这是首次鉴定出在生理条件下产生的单个含kringle的抗血管生成纤溶酶原片段。
Tumor or tumor-associated cells cleave circulating plasminogen into three or four kringle-containing antiangiogenic fragments, collectively referred to as angiostatin. Angiostatin blocks tumor growth and metastasis by preventing the growth of endothelial cells that are critical for tumor vascularization. Here, we show that cancer and normal cells convert plasminogen into a novel 22 kDa fragment (p22). Production of this plasminogen fragment in a cell-free system has allowed characterization of the structure and activity of the protein. p22 consists of amino acid residues 78-180 of plasminogen and therefore embodies the first plasminogen kringle (residues 84-162) as well as additional N- and C-terminal residues. Circular dichroism and intrinsic fluorescence spectrum analysis have defined structural differences between p22 and recombinant plasminogen kringle 1 (rK1), therefore suggesting a unique conformation for kringle 1 within p22. Proliferation of capillary endothelial cells but not cells of other lineages was selectively inhibited by p22 in vitro. In addition, p22 prevented vascular growth of chick chorioallantoic membranes (CAMs) in vivo. Furthermore, administration of p22 at low dose suppressed the growth of murine Lewis lung carcinoma (LLC) metastatic foci in vivo. This is the first identification of a single kringle-containing antiangiogenic plasminogen fragment produced under physiological conditions.