抗血管生成剂TNP - 470使内皮细胞生长停滞需要p53和p21CIP/WAF。
The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest.
作者信息
Yeh J R, Mohan R, Crews C M
机构信息
Departments of Molecular, Cellular, and Developmental Biology, and Pharmacology, Yale University, New Haven, CT 06520-8103, USA.
出版信息
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12782-7. doi: 10.1073/pnas.97.23.12782.
Abstract
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.
摘要
鉴于关键细胞周期调节因子的普遍表达，将内皮细胞周期作为一种抗血管生成策略一直颇具难度。在此，我们表明抗血管生成药物TNP-470具有显著的细胞类型特异性，因为它在内皮细胞中诱导细胞周期蛋白依赖性激酶抑制剂p21（CIP/WAF）的表达，而在胚胎或成年成纤维细胞中则不会。此外，从p53（-/-）和p21（CIP/WAF-/-）小鼠分离的原代内皮细胞对TNP-470的细胞生长抑制活性具有抗性。我们还证明，在碱性成纤维细胞生长因子角膜微袋血管生成试验中，p21（CIP/WAF-/-）小鼠对TNP-470的抗血管生成活性具有抗性。我们得出结论，TNP-470通过一种独特的机制在内皮细胞中诱导p53激活，导致p21（CIP/WAF）表达及随后的生长停滞。
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