Strömblad S, Becker J C, Yebra M, Brooks P C, Cheresh D A
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
J Clin Invest. 1996 Jul 15;98(2):426-33. doi: 10.1172/JCI118808.
Induction of p53 activity in cells undergoing DNA synthesis represents a molecular conflict that can lead to apoptosis. During angiogenesis, proliferative endothelial cells become apoptotic in response to antagonists of integrin alphavbeta3 and this leads to the regression of angiogenic blood vessels, thereby blocking the growth of various human tumors. Evidence is presented that administration of alphavbeta3 antagonists during angiogenesis in vivo selectively caused activation of endothelial cell p53 and increased expression of the p53-inducible cell cycle inhibitor p21WAF1/CIP1. In vitro studies revealed that the ligation state of human endothelial cell alphavbeta3 directly influenced p53 activity and the bax cell death pathway. Specifically, agonists of endothelial cell alphavbeta3, but not other integrins, suppressed p53 activity, blocked p21WAF1/CIP1 expression, and increased the bcl-2/bax ratio, thereby promoting cell survival. Thus, ligation of vascular cell integrin alphavbeta3 promotes a critical and specific adhesion-dependent cell survival signal during angiogenesis leading to inhibition of p53 activity, decreased expression of p21WAF1/CIP1, and suppression of the bax cell death pathway.
在进行DNA合成的细胞中诱导p53活性代表了一种分子冲突，可导致细胞凋亡。在血管生成过程中，增殖的内皮细胞会因整合素αvβ3拮抗剂的作用而发生凋亡，这会导致血管生成血管的消退，从而阻断各种人类肿瘤的生长。有证据表明，在体内血管生成过程中给予αvβ3拮抗剂会选择性地导致内皮细胞p53活化，并增加p53诱导的细胞周期抑制剂p21WAF1/CIP1的表达。体外研究表明，人内皮细胞αvβ3的连接状态直接影响p53活性和bax细胞死亡途径。具体而言，内皮细胞αvβ3的激动剂而非其他整合素，可抑制p53活性，阻断p21WAF1/CIP1表达，并增加bcl-2/bax比值，从而促进细胞存活。因此，血管细胞整合素αvβ3的连接在血管生成过程中促进了一种关键且特定的依赖黏附的细胞存活信号，导致p53活性受到抑制、p21WAF1/CIP1表达降低以及bax细胞死亡途径受到抑制。
