An oncogenic role of sphingosine kinase
An oncogenic role of sphingosine kinase
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DOI：
10.1016/s0960-9822(00)00834-4
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发表时间：
2000-11-30
期刊：
影响因子：
9.2
通讯作者：
Vadas, MA
中科院分区：
文献类型：
--
作者：
Xia, P;Gamble, JR;Vadas, MA
鞘氨醇激酶（SphK）是一种高度保守的脂质激酶，其磷酸化鞘氨醇以形成鞘氨醇-1-磷酸（S1 P）。S1 P/SphK被认为是调节多种细胞功能的信号通路[1-3]，包括细胞生长、增殖和存活[4-8]。我们报告说，细胞过表达SphK酶活性增加，并获得转化的表型，所确定的焦点形成，在软琼脂中的菌落生长和NOD/SCID小鼠形成肿瘤的能力。这是第一次证明，野生型脂质激酶基因作为一个致癌基因。使用SphK的化学抑制剂或抑制酶激活的SphK突变体，我们发现SphK活性参与致癌H-Ras介导的转化，这表明Ras激活的新信号通路。这些发现不仅指出了一种新的转化信号通路，而且还指出了SphK抑制剂在癌症治疗中的潜力。
Sphingosine kinase (SphK) is a highly conserved lipid kinase that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). S1P/SphK has been implicated as a signalling pathway to regulate diverse cellular functions [1-3], including cell growth, proliferation and survival [4-8]. We report that cells overexpressing SphK have increased enzymatic activity and acquire the transformed phenotype, as determined by focus formation, colony growth in soft agar and the ability to form tumours in NOD/SCID mice. This is the first demonstration that a wild-type lipid kinase gene acts as an oncogene. Using a chemical inhibitor of SphK, or an SphK mutant that inhibits enzyme activation, we found that SphK activity is involved in oncogenic H-Ras-mediated transformation, suggesting a novel signalling pathway for Ras activation. The findings not only point to a new signalling pathway in transformation but also to the potential of SphK inhibitors in cancer therapy.