TUMOR-NECROSIS-FACTOR (TNF)-ALPHA ACTIVATES C-RAF-1 KINASE VIA THE P55 TNF RECEPTOR ENGAGING NEUTRAL SPHINGOMYELINASE
TUMOR-NECROSIS-FACTOR (TNF)-ALPHA ACTIVATES C-RAF-1 KINASE VIA THE P55 TNF RECEPTOR ENGAGING NEUTRAL SPHINGOMYELINASE
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DOI：
10.1002/j.1460-2075.1995.tb07099.x
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发表时间：
1995-03-15
期刊：
影响因子：
11.4
通讯作者：
BRACH, MA
中科院分区：
文献类型：
--
作者：
BELKA, C;WIEGMANN, K;BRACH, MA
tnf - α介导细胞增殖、功能激活和凋亡死亡，这取决于其浓度和靶细胞类型。目前，人们还不完全了解tnf - α触发这些反应的信号通路。我们在这里报道，TNF- α促进剂量依赖性和时间依赖性的磷酸化和c-raf-1激酶的激活，与I型p55 TNF受体（TNF- r）结合，c-raf-1激酶的激活被一种针对p55 TNF- r的激动性单克隆抗体复制。此外，人p55 TNF-R在小鼠b前70Z/3细胞中的异位表达足以使c-raf-1激酶被人tnf - α激活。通过抑制细胞内酸性鞘磷脂酶（SMase）的激活和使用I型TNF-R的缺失形式，表明中性而不是酸性SMase参与了tnf - α介导的磷酸化和c-raf激酶的激活。tnf α诱导的含有AP-1结合位点的异源启动子结构的转录激活也由I型p55 TNF-R介导。在这种情况下，转录的起始需要与c-raf-1激酶激活相同的细胞质结构域，并且在c-raf-1显性负突变体存在的情况下被释放。
TNF-alpha mediates proliferation, functional activation and apoptotic death of cells depending upon its concentration and target cell type. The signaling pathways used by TNF-alpha to mount these responses are, at present, not completely understood. We report here that TNF-alpha promotes dose- and time-dependent phosphorylation and activation of the c-raf-1 kinase engaging the type I p55 TNF receptor (TNF-R), c-raf-kinase activation was duplicated by an agonistic monoclonal antibody directed against the p55 TNF-R. Moreover, ectopic expression of the human p55 TNF-R in murine pre-B 70Z/3 cells was sufficient to confer c-raf-1-kinase activation by human TNF-alpha. By inhibiting intracellular activation of acidic sphingomyelinase (SMase) and by using deleted forms of the type I TNF-R it was shown that the neutral, but not the acidic SMase, participated in TNF-alpha-mediated phoshorylation and activation of the c-raf kinase. TNF-alpha-induced transcriptional activation of a heterologous promoter construct harboring the AP-1 binding site was also mediated by the type I p55 TNF-R. In this case the initiation of transcription required the same cytoplasmic domain as that responsible for activation of c-raf-1 kinase and was liberated in the presence of a dominant negative mutant of c-raf-1.