DIFFERENTIAL REGULATION OF SPHINGOMYELINASE AND CERAMIDASE ACTIVITIES BY GROWTH-FACTORS AND CYTOKINES - IMPLICATIONS FOR CELLULAR PROLIFERATION AND DIFFERENTIATION
DIFFERENTIAL REGULATION OF SPHINGOMYELINASE AND CERAMIDASE ACTIVITIES BY GROWTH-FACTORS AND CYTOKINES - IMPLICATIONS FOR CELLULAR PROLIFERATION AND DIFFERENTIATION
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DOI：
10.1074/jbc.270.40.23305
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发表时间：
1995-10-06
影响因子：
4.8
通讯作者：
KESTER, M
中科院分区：
文献类型：
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作者：
CORONEOS, E;MARTINEZ, M;KESTER, M
鞘氨醇是鞘脂代谢的产物，与蛋白激酶c无关的有丝分裂反应有关。在先前发表的数据中，利用血小板衍生生长因子（PDGF）诱导的血管平滑肌增殖的体外模型系统，我们已经证明鞘氨醇的增加是以神经酰胺形成的减少为代价的，这意味着神经酰胺酶活性的改变。为了探索生长因子刺激鞘氨醇形成的机制，我们开发并研究了一个评估神经酰胺酶活性的无细胞模型系统。我们现在报道，大鼠肾小球系膜细胞（一种平滑肌样周细胞）中的碱性膜相关神经酰胺酶活性被生长因子上调，显然是通过酪氨酸激酶磷酸化机制。PDGF还刺激鞘磷脂酶活性，产生足够的底物来驱动随后的神经酰胺酶反应，炎性细胞因子，包括白细胞介素-1和肿瘤坏死因子- α，刺激鞘磷脂酶但不刺激神经酰胺酶活性，结果与神经酰胺的细胞积累一致，凋亡，分化第二信使，有丝分裂血管收缩肽如内皮素-1既不刺激鞘磷脂酶也不刺激神经酰胺酶活性。神经酰胺酶活性抑制剂n-油基乙醇胺可降低PDGF-，但不能抑制内皮素-1刺激的增殖。因此，我们得出结论，在系膜细胞中，生长因子，而不是血管收缩肽或细胞因子，部分通过神经酰胺酶介导的鞘氨酸形成诱导有丝分裂。
Sphingosine is a product of sphingolipid metabolism that has been linked to a protein kinase C-independent mitogenic response. In previously published data, utilizing an in vitro model system for platelet-derived growth factor (PDGF)-induced vascular smooth muscle proliferation, we have demonstrated that sphingosine is increased at the expense of a concomitant decrease in ceramide formation, implicating an altered ceramidase activity. To explore mechanisms of growth factor stimulated sphingosine formation, we have developed and investigated a cell free model system assessing ceramidase activity. We now report that an alkaline, membrane-associated, ceramidase activity in the rat glomerular mesangial cell, a smooth muscle-like pericyte, is up-regulated by growth factors, apparently via a tyrosine kinase phosphorylation mechanism. PDGF also stimulated sphingomyelinase activity which generates sufficient substrate to drive the subsequent ceramidase reaction, Inflammatory cytokines, including interleukin-1, and tumor necrosis factor-alpha, stimulated sphingomyelinase but not ceramidase activity, a result consistent with the cellular accumulation of the ceramide, apoptidic, differentiating second messenger, Mitogenic vasoconstrictor peptides such as endothelin-1 stimulated neither sphingomyelinase nor ceramidase activities, An inhibitor of ceramidase activity, N-oleoylethanolamine, reduced PDGF- but not endothelin-1-stimulated proliferation. Thus, we conclude that, in mesangial cells, growth factors but not vasoconstrictor peptides or cytokines induce mitogenesis, in part, through ceramidase-mediated sphingosine formation.