p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase
p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase
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DOI：
10.1126/science.1126391
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发表时间：
2006-08-18
期刊：
影响因子：
56.9
通讯作者：
Green, Michael R.
中科院分区：
文献类型：
--
作者：
Teodoro, Jose G.;Parker, Albert E.;Green, Michael R.
最近的证据表明，抗血管生成治疗是敏感的p53状态在肿瘤中，暗示的作用，p53在调节血管生成。在这里，我们表明，p53转录激活α（II）胶原蛋白脯氨酰-4-羟化酶[α（II）PH]基因，导致4型和18型胶原蛋白的抗血管生成片段的细胞外释放。来自异位表达p53或α（II）PH的细胞的条件培养基选择性地抑制原代人内皮细胞的生长。当表达细胞内或外源性交付，α（II）PH显着抑制小鼠肿瘤生长。我们的研究结果揭示了p53肿瘤抑制通路和抗血管生成胶原片段的合成之间的遗传和生化联系。
Recent evidence suggests that antiangiogenic therapy is sensitive to p53 status in tumors, implicating a role for p53 in the regulation of angiogenesis. Here we show that p53 transcriptionally activates the alpha(II) collagen prolyl-4-hydroxylase [alpha(II) PH] gene, resulting in the extracellular release of antiangiogenic fragments of collagen type 4 and 18. Conditioned media from cells ectopically expressing either p53 or alpha(II) PH selectively inhibited growth of primary human endothelial cells. When expressed intracellularly or exogenously delivered, alpha(II) PH significantly inhibited tumor growth in mice. Our results reveal a genetic and biochemical linkage between the p53 tumor suppressor pathway and the synthesis of antiangiogenic collagen fragments.