Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27.
Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27.
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DOI：
10.1007/s11010-009-0359-z
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发表时间：
2010-05
影响因子：
4.3
通讯作者：
Hall, Jennifer L.
中科院分区：
文献类型：
--
作者：
Lee, Sangjin;Nguyen, Tri M. Bui;Kovalenko, Dmitry;Adhikari, Neeta;Grindle, Suzanne;Polster, Sean P.;Friesel, Robert;Ramakrishnan, Sundaram;Hall, Jennifer L.
Sprouty 1（Spry 1）是FGF信号传导的保守拮抗剂。本研究的目的是进一步探讨Spry 1抑制内皮细胞增殖的下游机制。上调Spry 1表达可抑制基质胶上的小管形成（n = 6，P < 0.001）。这与通过BrdU掺入（n = 6，P < 0.001）测量的增殖降低以及细胞周期蛋白依赖性激酶抑制剂1A（CDKN 1A），p21和细胞周期蛋白依赖性激酶抑制剂1B（CDKN 1B），p27的蛋白表达增加有关。使用靶向人血管生成阵列的转录分析显示，在Spry 1上调后，抗血管生成因子、丝氨酸蛋白酶抑制剂肽酶抑制剂clad F（Serpinf 1）增加>2倍，促血管生成因子fms相关酪氨酸激酶1（FLT 1）、血管生成素2（Ang-2）和胎盘生长因子（PGF）减少>2倍（n = 2）。为了确定上游机制，可能会调节内源性Spry 1，我们进行了搜索的启动子区上游的响应元件。这一搜索导致多个简并缺氧反应元件的鉴定。低氧组Spry 1蛋白表达显著增加（n = 8，P < 0.01）。这些发现揭示了与Spry 1抗增殖反应相关的下游信号通路，并提供了缺氧刺激Spry 1表达的新证据。
Sprouty1 (Spry1) is a conserved antagonist of FGF signaling. The goal of this study was to further explore the downstream mechanisms governing Spry1 inhibition of endothelial cell proliferation. Up-regulation of Spry1 in HUVECs inhibited tube formation on Matrigel (n = 6, P < 0.001). This was associated with decreased proliferation as measured by BrdU incorporation (n = 6, P < 0.001) and increased protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A), p21 and cyclin-dependent kinase inhibitor 1B (CDKN1B), p27. A transcriptional analysis using a targeted human angiogenesis array following up-regulation of Spry1 demonstrated a >2-fold increase in an anti-angiogenic factor, serpin peptidase inhibitor, clad F (Serpinf1), and a >2-fold decrease in pro-angiogenic factors fms-related tyrosine kinase 1 (FLT1), angiopoietin2 (Ang-2), and placental growth factor (PGF) (n = 2). To define upstream mechanisms that may regulate endogenous Spry1, we performed a search for responsive elements upstream of the promoter region. This search resulted in the identification of multiple degenerate hypoxia responsive elements. Exposure to hypoxia resulted in a significant increase in Spry1 expression (n = 8, P < 0.01). These findings shed new light on downstream signaling pathways associated with Spry1 anti-proliferative responses, and provide new evidence that hypoxia stimulates Spry1 expression.
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