Down syndrome candidate region 1-like 1 (DSCR1-L1) mimics the inhibitory effects of DSCR1 on calcineurin signaling in endothelial cells and inhibits angiogenesis
Down syndrome candidate region 1-like 1 (DSCR1-L1) mimics the inhibitory effects of DSCR1 on calcineurin signaling in endothelial cells and inhibits angiogenesis
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DOI：
10.1016/j.jss.2006.10.011
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发表时间：
2007-09-01
影响因子：
2.2
通讯作者：
Yoon, Sam S.
中科院分区：
文献类型：
--
作者：
Gollogly, Lila K.;Ryeom, Sandra W.;Yoon, Sam S.
在内皮细胞中，血管内皮生长因子（VEGF）与VEGF受体2的结合导致丝氨酸/苏氨酸磷酸酶钙调神经磷酸酶的活化、活化T细胞核因子（NF-AT）转录因子的去磷酸化、NF-AT向细胞核的易位以及血管生成相关基因如考克斯-2的表达。唐氏综合征候选区I（DSCR 1）通过NF-AT核转位反式激活，随后抑制钙调神经磷酸酶活性，形成负反馈环。虽然DSCR 1作为VEGF-钙调神经磷酸酶介导的血管生成的内源性抑制剂在内皮细胞中具有明确的作用，但DSCR 1家族成员DSCR 1样1（DSCR 1-L1）的功能尚未在内皮细胞中研究。在这里，我们表明，一组促血管生成因子，包括VEGF，碱性成纤维细胞生长因子（bFGF），血管生成素1，肝细胞生长因子，以及三碘-L-甲状腺原氨酸（T1），不诱导DSCR 1-L1在内皮细胞中的上调，而VEGF有力地上调DSCR 1。为了研究DSCR 1-L1对内皮细胞功能的影响，我们将该基因克隆到慢病毒载体中，并在人脐静脉内皮细胞中过表达DSCR 1-L1。组成性DSCR 1-L1过表达阻止了NF-ATcl响应VEGF的核转位，强调了其作为钙调磷酸酶抑制剂的作用。此外，与对照病毒感染的细胞相比，DSCR 1-L1转导的细胞分别抑制VEGF诱导的内皮细胞迁移、增殖和管形成36%、77%和39%。在转化的内皮细胞系Sven I-ras中过表达DSCR 1-L1也导致增殖降低。我们的研究结果表明，DSCR 1-L1是组成型表达的内皮细胞和DSCR 1在抑制钙调磷酸酶活性和抑制VEGF介导的血管生成的行为相似。(c)2007年爱思唯尔公司All rights reserved.
In endothelial cells, binding of vascular endothelial growth factor (VEGF) to VEGF receptor 2 leads to the activation of the serine/threonine phosphatase calcineurin, dephosphorylation of the nuclear factor of activated T-cells (NF-AT) transcription factors, translocation of NF-AT to the nucleus, and expression of angiogenesis-related genes such as Cox-2. Down syndrome candidate region I (DSCR1) is transactivated by NF-AT nuclear translocation, and subsequently inhibits calcineurin activity, forming a negative feedback loop. While DSCR1 has a clearly defined role as an endogenous inhibitor of VEGF-calcineurinmediated angiogenesis in endothelial cells, the function of the DSCR1 family member, DSCRl-like 1 (DSCR1-L1), has not yet been investigated in endothelial cells. Here we show that a panel of pro-angiogenic factors, including VEGF, basic fibroblast growth factor (bFGF), angiopoietin 1, hepatocyte growth factor, as well as triiodo-L-thyronine (T,), does not induce DSCR1-L1 up-regulation in endothelial cells, while VEGF potently up-regulates DSCR1. To investigate the effects of DSCR1-L1 on endothelial cell function, we cloned the gene into a lentiviral vector and over-expressed DSCR1-L1 in human umbilical vein endothelial cells. Constitutive DSCR1-L1 overexpression prevented the nuclear translocation of NF-ATcl in response to VEGF, underscoring its role as a calcineurin inhibitor. Additionally, DSCR1-L1-transduced cells inhibited VEGF-induced endothelial cell migration, proliferation, and tube formation by 36, 77, and 39%, respectively, compared to cells infected with control virus. Overexpression of DSCR1-L1 in the transformed endothelial cell line Sven I ras also resulted in decreased proliferation. Our findings demonstrate that DSCR1-L1 is constitutively expressed in endothelial cells and acts similar to DSCR1 in inhibiting calcineurin activity and restraining VEGF-mediated angiogenesis. (c) 2007 Elsevier Inc. All rights reserved.