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Abstract：
Anti-angiogenesis serves as an effective tumor therapy approach. In a previous study, we found that β3-endonexin expressed in vascular endothelial cells was involved in promoting proliferation and angiogenesis partially by facilitating VEGF expression. However, it still remains unclear if β3-endonexin in vascular endothelial cells also employs other mechanisms in regulating angiogenesis. In this study, we utilized a β3-endonexin mutant (M2) carrying a defective nuclear localization sequence to disrupt its nuclear localization and evaluated its ability to promote HUVEC proliferation and formation of tube-like vascular structures. In addition, we performed yeast 2-hybrid assay to identify potential functional effectors of β3-endonexin. We found that both wild type β3-endonexin and the M2 mutant could localize to centrosomes in HUVECs and both were able to promote HUVEC proliferation and formation of vascular structures. However, the M2 mutant failed to promote VEGF expression in HUVECs. Further, we found that both wild type β3-endonexin and the M2 mutant were capable of binding to ninein, a centrosomal protein with a proangiogenic effect. Knockdown of ninein in HUVECs impeded centrosome localization of wild type β3-endonexin and the M2 mutant and inhibited HUVEC proliferation and formation of vascular structures. Taken together, these findings suggest that β3-endonexin interacts with centrosome ninein and contributes to HUVEC proliferation and formation of vascular structures.
摘要：
抗血管生成是一种有效的肿瘤治疗方法。在之前的研究中,我们发现,在血管内皮细胞中表达的β3-内皮连接蛋白通过促进VEGF的表达部分参与促进增殖和血管生成.然而,目前尚不清楚血管内皮细胞中的β3-内皮素是否也有其他机制来调节血管生成.在这项研究中,我们利用携带有缺陷的核定位序列的β3-内切酶突变体(M2)破坏其核定位,并评估其促进HUVEC增殖和管状血管结构形成的能力.此外,我们进行了酵母2-杂交试验以鉴定β3-内切酶的潜在功能效应子.我们发现野生型β3-内切酶和M2突变体都可以定位于HUVEC的中心体，并且都能够促进HUVEC的增殖和血管结构的形成。然而,M2突变体未能促进HUVECs中VEGF的表达.Further,我们发现野生型β3-内切酶和M2突变体都能够与ninein结合，具有促血管生成作用的中心体蛋白。HUVEC中ninein的敲低阻碍了野生型β3-endonexin和M2突变体的中心体定位，并抑制了HUVEC的增殖和血管结构的形成。一起来看,这些研究结果表明,β3-内联蛋白与中心体ninein相互作用,有助于HUVEC增殖和血管结构的形成.
