High efficacy and minimal peptide required for the anti-angiogenic and anti-hepatocarcinoma activities of plasminogen K5.
High efficacy and minimal peptide required for the anti-angiogenic and anti-hepatocarcinoma activities of plasminogen K5.
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纤溶酶原 K5 的抗血管生成和抗肝癌活性所需的高效且最少的肽
DOI：
10.1111/j.1582-4934.2009.01004.x
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发表时间：
2010-10
影响因子：
5.3
通讯作者：
Gao G
中科院分区：
文献类型：
--
作者：
Yang X;Cai W;Xu Z;Chen J;Li C;Liu S;Yang Z;Pan Q;Li M;Ma J;Gao G
Kringle 5(K5) 是人纤溶酶原的第五个三环结构域，其抗血管生成活性比包含纤溶酶原前四个三环片段的血管抑制素更有效。我们最近的研究表明，K5 通过抗血管生成来抑制肝癌的生长。为了找到 K5 的抗血管生成和抗肿瘤活性所需的高效且最少的肽序列，产生了 K5 的两个缺失突变体。完整K5(Pro452-Ala542)的kringle结构域外部的氨基酸残基被删除，形成K5mut1(Cys462-Cys541)。残基Cys462再次被删除，形成K5mut2(Met463-Cys541)。 K5mut1特异性抑制内皮细胞的增殖、迁移和诱导凋亡，其活性比K5明显增强两倍。在 HepA 移植和 Bel7402 异种移植肝癌小鼠模型中，腹腔注射 K5mut1 比 K5 产生更有效的肿瘤生长抑制和微血管密度降低。这些结果表明 K5mut1 比完整的 K5 具有更有效的抗血管生成活性。 K5mut2仅缺少K5mut1的氨基末端半胱氨酸，完全丧失了活性，表明kringle结构域对于K5的活性至关重要。当K5的NH2末端Kringle结构域外的5个酸性氨基酸被5个丝氨酸残基(K5mut3)取代时，活性增强至K5mut1水平。酸性氨基酸的屏蔽作用可以解释为什么K5mut1具有更高的活性。 K5、K5mut1和K5mut3具有特征性β折叠谱，而K5mut2采用无规卷曲结构。这些结果表明，高效的K5mut1是K5的最小活性肽序列，可能具有治疗肝癌的潜力。
Kringle 5(K5) is the fifth kringle domain of human plasminogen and its anti-angiogenic activity is more potent than angiostatin that includes the first four kringle fragment of plasminogen. Our recent study demonstrated that K5 suppressed hepatocarcinoma growth by anti-angiogenesis. To find high efficacy and minimal peptide sequence required for the anti-angiogenic and anti-tumour activities of K5, two deletion mutants of K5 were generated. The amino acid residues outside kringle domain of intact K5 (Pro452-Ala542) were deleted to form K5mut1(Cys462-Cys541). The residue Cys462 was deleted again to form K5mut2(Met463-Cys541). K5mut1 specifically inhibited proliferation, migration and induced apoptosis of endothelial cells, with an apparent two-fold enhanced activity than K5. Intraperitoneal injection of K5mut1 resulted in more potent tumour growth inhibition and microvessel density reduction than K5 both in HepA-grafted and Bel7402-xenografted hepatocarcinoma mouse models. These results suggested that K5mut1 has more potent anti-angiogenic activity than intact K5. K5mut2, which lacks only the amino terminal cysteine of K5mut1, completely lost the activity, suggesting that the kringle domain is essential for the activity of K5. The activity was enhanced to K5mut1 level when five acidic amino acids of K5 in NH2 terminal outside kringle domain were replaced by five serine residues (K5mut3). The shielding effect of acidic amino acids may explain why K5mut1 has higher activity. K5, K5mut1 and K5mut3 held characteristic β-sheet spectrum while K5mut2 adopted random coil structure. These results suggest that K5mut1 with high efficacy is the minimal active peptide sequence of K5 and may have therapeutic potential in liver cancer.
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影响因子：
4
作者：
Cai, WB;Ma, JF;Gao, GQ
通讯作者：
Gao, GQ
DOI：
10.1093/protein/7.7.895
发表时间：
1994-07-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
LOKKER, NA;PRESTA, LG;GODOWSKI, PJ
通讯作者：
GODOWSKI, PJ
影响因子：
4.8
作者：
Gao, GQ;Li, Y;Ma, JX
通讯作者：
Ma, JX
DOI：
10.1073/pnas.95.11.6367
发表时间：
1998-05-26
影响因子：
11.1
作者：
Griscelli, F;Li, H;Lu, H
通讯作者：
Lu, H
影响因子：
64.8
作者：
MCLEAN, JW;TOMLINSON, JE;LAWN, RM
通讯作者：
LAWN, RM