Iurlaro Monica, Demontis Fabio, Corada Monica, Zanetta Lucia, Drake Cristopher, Gariboldi Manuela, Peiro Sandra, Cano Amparo, Navarro Pilar, Cattelino Anna, Tognin Simona, Marchisio Pier Carlo, Dejana Elisabetta
Italian Foundation for Cancer Research, Institute of Molecular Oncology, Milan, Italy.
Am J Pathol. 2004 Jul;165(1):181-9. doi: 10.1016/S0002-9440(10)63287-7.
Survivin is strongly expressed in embryonic organs and in tumor cells but is low or absent in differentiated normal tissues. Resting endothelium expresses low levels of survivin but can up-regulate its synthesis on activation to proliferate. The mechanisms responsible for survivin down-regulation in resting conditions are still unknown. We report here that confluence and vascular endothelial-cadherin (VE-cadherin) expression induce contact inhibition of cell growth and survivin down-regulation in the endothelium. Using beta-catenin null and positive isogenic endothelial cell lines we found that the effect requires beta-catenin expression and its association to VE-cadherin cytoplasmic tail. Furthermore, in allantois organ cultures, survivin expression is up-regulated in areas of growing vessels where VE-cadherin is partially dismantled from junctions or in VE-cadherin -/- specimens. Overall, these data indicate that VE-cadherin and beta-catenin may negatively regulate survivin synthesis in endothelial cells. Consistently, in epidermal and pancreatic cell lines or ovarian tumors, epithelial-cadherin (E-cadherin) and survivin expression is inversely related, suggesting a non-cell-specific role of cadherins in reducing survivin synthesis.
存活素在胚胎器官和肿瘤细胞中强烈表达，但在分化的正常组织中表达较低或缺失。静息内皮细胞表达低水平的存活素，但在激活增殖时可上调其合成。静息状态下存活素下调的机制仍不清楚。我们在此报告，汇合和血管内皮钙黏蛋白（VE-钙黏蛋白）表达可诱导内皮细胞生长的接触抑制和存活素下调。使用β-连环蛋白缺失和阳性的同基因内皮细胞系，我们发现该效应需要β-连环蛋白表达及其与VE-钙黏蛋白细胞质尾部的结合。此外，在尿囊器官培养中，在生长血管区域，当VE-钙黏蛋白从连接处部分拆解或在VE-钙黏蛋白基因敲除标本中，存活素表达上调。总体而言，这些数据表明，VE-钙黏蛋白和β-连环蛋白可能在内皮细胞中负向调节存活素合成。同样，在表皮和胰腺细胞系或卵巢肿瘤中，上皮钙黏蛋白（E-钙黏蛋白）和存活素表达呈负相关，表明钙黏蛋白在降低存活素合成方面具有非细胞特异性作用。
