The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest
The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest
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DOI：
10.1073/pnas.97.23.12782
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发表时间：
2000-11-07
影响因子：
11.1
通讯作者：
Crews, CM
中科院分区：
文献类型：
--
作者：
Yeh, JRJ;Mohan, R;Crews, CM
考虑到关键的细胞周期调节因子的普遍表达，将内皮细胞周期作为抗血管生成的策略一直是困难的。在这里，我们表明，抗血管生成药物TNP-470表现出显著的细胞类型特异性，因为它诱导了p21(CIP/WAF)的表达，p21是一种细胞周期蛋白依赖的激酶抑制物。在内皮细胞中，但在胚胎或成年成纤维细胞中不存在。此外，从P53(-/-)和p21(CIP/WAF-/-)小鼠分离的原代内皮细胞对TNP-470的细胞抑制活性具有抵抗力。在碱性成纤维细胞生长因子角膜微袋血管生成实验中，我们还证明了p21(CIP/WAF-/-)小鼠对TNP-470的抗血管生成活性具有抵抗力。我们得出结论，TNP-470通过一种独特的机制诱导内皮细胞中P53的激活，从而导致p21(CIP/WAF)的表达和随后的生长停滞。
Targeting the endothelial cell cycle as an antiangiogenic strategy has been difficult given the ubiquitous expression of critical cell cycle regulators. Here, we show that the antiangiogenic drug TNP-470 displays striking cell-type specificity insofar as it induces the expression of p21(CIP/WAF), a cyclin-dependent kinase inhibitor. in endothelial cells but not in embryonic or adult fibroblasts. Moreover, primary endothelial cells isolated from p53(-/-) and p21(CIP/WAF-/-) mice are resistant to the cytostatic activity of TNP-470. We also demonstrate that p21(CIP/WAF-/-) mice are resistant to the antiangiogenic activity of TNP-470 in the basic fibroblast growth factor corneal micropocket angiogenesis assay. We conclude that TNP-470 induces p53 activation through a unique mechanism in endothelial cells leading to p21(CIP/WAF) expression and subsequent growth arrest.