Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells.
Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells.
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DOI：
10.1016/j.bbrc.2008.01.132
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发表时间：
2008-04
影响因子：
3.1
通讯作者：
S. Schwalm;F. Döll;I. Römer;Svetlana Bubnova;J. Pfeilschifter;A. Huwiler
中科院分区：
文献类型：
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作者：
S. Schwalm;F. Döll;I. Römer;Svetlana Bubnova;J. Pfeilschifter;A. Huwiler
鞘氨醇激酶（SK）催化鞘氨醇-1-磷酸的产生，鞘氨醇-1-磷酸进而调节细胞反应，例如增殖和迁移。在这里，我们表明，暴露于缺氧的人内皮细胞系EA.hy926刺激增加SK-1，但不是SK-2，mRNA，蛋白质的表达和活性。这种效应是由于刺激SK-1启动子活性，其中包含两个推定的缺氧诱导因子反应元件（HRE）。通过缺失两个HRE中的一个，缺氧诱导的启动子激活被废除。低氧可上调HIF-1α和HIF-2α的表达，并通过siRNA选择性地去除HIF-1α和HIF-2α，促进SK-1基因的转录。缺氧刺激的SK-1上调在功能上与增加的迁移偶联，因为通过siRNA选择性耗尽SK-1而不是SK-2消除了迁移反应。总之，这些数据表明，缺氧上调SK-1活性，并导致内皮细胞的迁移能力加快。因此，SK-1可以作为一个有吸引力的治疗靶点，以治疗与增加的内皮细胞迁移和血管生成相关的疾病，如癌症的生长和进展。
Sphingosine kinases (SK) catalyze the production of sphingosine-1-phosphate which in turn regulates cell responses such as proliferation and migration. Here, we show that exposure of the human endothelial cell line EA.hy 926 to hypoxia stimulates a increased SK-1, but not SK-2, mRNA, protein expression, and activity. This effect was due to stimulated SK-1 promoter activity which contains two putative hypoxia-inducible factor-responsive-elements (HRE). By deletion of one of the two HREs, hypoxia-induced promoter activation was abrogated. Furthermore, hypoxia upregulated the expression of HIF-1α and HIF-2α, and both contributed to SK-1 gene transcription as shown by selective depletion of HIF-1α or HIF-2α by siRNA. The hypoxia-stimulated SK-1 upregulation was functionally coupled to increased migration since the selective depletion of SK-1, but not of SK-2, by siRNAs abolished the migratory response. In summary, these data show that hypoxia upregulates SK-1 activity and results in an accelerated migratory capacity of endothelial cells. SK-1 may thus serve as an attractive therapeutic target to treat diseases associated with increased endothelial migration and angiogenesis such as cancer growth and progression.