Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P
Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P
复制标题
DOI：
10.1096/fj.05-5689com
复制
发表时间：
2006-09-01
期刊：
影响因子：
4.8
通讯作者：
Mao, Cungui
中科院分区：
文献类型：
--
作者：
Xu, Ruijuan;Jin, Junfei;Mao, Cungui
鞘氨醇-1-磷酸(S1P)是一种鞘糖脂代谢物，可促进细胞增殖和存活，而其前体鞘氨醇具有相反的作用。然而，对它们的监管仍有许多未知之处。在这里，我们发现了一种新的人类神经酰胺酶(HaCER2)，它通过控制神经酰胺的水解来调节鞘氨醇和S1P的水平。HaCER2定位于高尔基复合体，在胎盘中高表达。HaCER2的高异位表达导致高尔基复合体的碎裂和由于鞘氨醇积累而导致的HeLa细胞生长停滞。在无血清条件下，异位低表达haCER2可增加S1P而不积聚鞘氨醇，促进细胞增殖。这种增殖作用可被S1P形成的抑制剂二甲基鞘氨醇或RNA干扰(RNAi)介导的S1P(1)抑制，S1P(1)是S1P的G蛋白偶联受体。RNAi介导的haCER2下调增强了血清剥夺诱导的HeLa细胞的生长停滞和凋亡，外源性S1P抑制了这一作用。血清剥夺可上调HeLa细胞中haCER2基因的表达和活性。在一些肿瘤中，haCER2的mRNA也表达上调。综上所述，这些结果表明haCER2对于S1P和S1P介导的细胞增殖和存活的产生是重要的，但其过度表达可能由于神经鞘氨醇的积累而导致细胞生长停滞。-Xu，R.，jin，J.，Hu，W.，Sun，W.，Bielawski，J.，Szulc，Z.，Taha，T.，Obeid，L.M.，Mao，C.Golgi碱性神经酰胺酶通过控制鞘氨醇和S1P水平来调节细胞的增殖和存活
Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, promotes cell proliferation and survival whereas its precursor, sphingosine, has the opposite effects. However, much remains unknown about their regulation. Here we identify a novel human ceramidase (haCER2) that regulates the levels of both sphingosine and S1P by controlling the hydrolysis of ceramides. haCER2 is localized to the Golgi complex and is highly expressed in the placenta. High ectopic expression of haCER2 caused fragmentation of the Golgi complex and growth arrest in HeLa cells due to sphingosine accumulation. Low ectopic expression of haCER2 increased S1P without sphingosine accumulation, promoting cell proliferation in serum-free medium. This proliferative effect was suppressed by dimethylsphingosine, an inhibitor of the S1P formation, or by the RNA interference (RNAi) - mediated inhibition of S1P(1), a G-protein-coupled receptor for S1P. The RNAi-mediated down-regulation of haCER2 enhanced the serum deprivation-induced growth arrest and apoptosis of HeLa cells, which was inhibited by addition of exogenous S1P. Serum deprivation up-regulated both haCER2 mRNA and activity in HeLa cells. haCER2 mRNA is also up-regulated in some tumors. Taken together, these results suggest that haCER2 is important for the generation of S1P and S1P-mediated cell proliferation and survival, but that its overexpression may cause cell growth arrest due to an accumulation of sphingosine. - Xu, R., Jin, J., Hu, W., Sun, W., Bielawski, J., Szulc, Z., Taha, T., Obeid, L. M., Mao, C. Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P