鞘氨醇激酶1
MAPK/ERK通路
细胞生物学
下调和上调
蛋白激酶B
血管生成
化学
PI3K/AKT/mTOR通路
细胞生长
基因敲除
S1PR1型
p38丝裂原活化蛋白激酶
信号转导
鞘氨醇
1-磷酸鞘氨醇
癌症研究
生物
血管内皮生长因子A
受体
血管内皮生长因子
细胞凋亡
生物化学
血管内皮生长因子受体
基因
作者
Zhan Gao,Hua Wang,Fengjun Xiao,Xuefeng Shi,Yi-Kun Zhang,Qin Qin Xu,Xiaoyan Zhang,Xiaoqin Ha,Lisheng Wang
标识
DOI:10.1016/j.biocel.2016.02.018
摘要
Angiogenesis is one of the most important components of embryonic organ formation and vessel growth after birth. Sphingosine kinase 1 (Sphk1) and S1P has been confirmed to participate in various cell signaling pathways and physiological processes including neovascularisation. However, the mechanisms that Sphk1/S1P regulates neovascularisation remain unclear. In this study, we elucidated that Sphk1/S1P upregulates sirtuin 1 (SIRT1), a NAD+ dependent deacetylases protease which exerts multiple cellular functions, to regulate the proliferation and migration of endothelial cells. By using CCK8 and Transwell assays, we demonstrated that Sphk1 and SIRT1 knockdown could significantly decrease proliferation and migration of HUVEC cells. Sphk1 inhibition results in SIRT1 downregulation which could be reversed by exogenous S1P in HUVEC cells. Treatment of HUVECs with S1P reverses the impaired proliferation and migration caused by SIRT1 knockdown. Furthermore, Sphk1 knockdown inhibits the phosphorylation of P38 MAPK, ERK and AKT. Treatment of HUVECs with PD98059, SB203580 and Wortmannin, which are the inhibitors of ERK, P38 MAPK and AKT respectively, resulted in decreased SIRT1 expression and reduced migration of HUVEC cells. Thus, we conclude that Sphk1/S1P induces SIRT1 upregulation through multiple pathways including P38 MAPK, ERK and AKT signals. This is the first report to disclose the existence and roles of Sphk1/S1P/SIRT1 axis in regulation of endothelial cell proliferation and migration, which may provide a theoretical basis for angiogenesis.
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