Inhibition of Fas (CD95) expression and Fas-mediated apoptosis by oncogenic Ras.
Inhibition of Fas (CD95) expression and Fas-mediated apoptosis by oncogenic Ras.
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发表时间：
1998-08
期刊：
影响因子：
11.2
通讯作者：
R. Fenton;J. Hixon;P. Wright;A. Brooks;T. Sayers
中科院分区：
文献类型：
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作者：
R. Fenton;J. Hixon;P. Wright;A. Brooks;T. Sayers
ras癌基因通过激活导致异常生长调节的信号转导途径在癌症的多步骤进展中起重要作用。尽管这些效应中有许多是细胞自主的，但ras癌基因也调节改变宿主/肿瘤相互作用的基因的表达。现在，我们通过证明致癌Ras抑制Fas基因的表达，并使Ras转化细胞抵抗Fas诱导的细胞凋亡，扩展了Ras促进肿瘤存活的机制。一组Ras转化的克隆与未转化的亲本细胞系相比，表现出Fas mRNA和Fas细胞表面表达的显着抑制。Fas的表达诱导的IFN-γ +肿瘤坏死因子α的存在下培养，然而，Ras转化体中达到的最大水平是约10倍低于未转化细胞的水平。而未转化的细胞对交联表面Fas诱导的凋亡性死亡敏感（特别是在细胞因子处理后），Ras转化的细胞即使在最严格的测定条件下也对Fas诱导的死亡具有很强的抗性。为了证明这种耐药性是由致癌Ras介导的，而不是由次级遗传事件介导的，使用高效逆转录病毒转导技术产生Ras转化的细胞库。感染后6天，转化池进行了测定，并表现出Fas基因表达和Fas介导的细胞凋亡显着减少。致癌Ras并没有促进细胞凋亡的一般阻力，因为异位表达Fas的cDNA在Ras转化细胞恢复敏感性Fas诱导的细胞凋亡。这些数据表明，致癌Ras抑制Fas基因表达的基础水平，虽然细胞因子信号转导途径在这些细胞中是功能性的，但表面Fas表达水平仍低于诱导细胞凋亡所需的阈值。这些数据确定了Ras转化的细胞可以逃避宿主介导的免疫破坏的机制。
The ras oncogene plays an important role in the multistep progression to cancer by activation of signal transduction pathways that contribute to aberrant growth regulation. Although many of these effects are cell autonomous, the ras oncogene also regulates the expression of genes that alter host/tumor interactions. We now extend the mechanisms through which ras promotes tumor survival by demonstrating that oncogenic Ras inhibits expression of the fas gene and renders Ras-transformed cells resistant to Fas-induced apoptosis. A panel of Ras-transformed clones exhibited a marked inhibition in fas mRNA and Fas cell surface expression as compared with untransformed parental cell lines. Fas expression was induced by culture in the presence of IFN-gamma + tumor necrosis factor alpha; however, the maximal level attained in Ras transformants was approximately 10-fold below the level of untransformed cells. Whereas untransformed cells were sensitive to apoptotic death induced by cross-linking surface Fas (especially after cytokine treatment), Ras-transformed cells were very resistant to Fas-induced death even under the most stringent assay conditions. To demonstrate that this resistance was mediated by oncogenic Ras and not secondary genetic events, pools of Ras-transformed cells were generated using a highly efficient retroviral transduction technique. Transformed pools were assayed 6 days after infection and demonstrated a marked decrease in fas gene expression and Fas-mediated apoptosis. Oncogenic Ras did not promote general resistance to apoptosis, because ectopic expression of a fas cDNA in Ras-transformed cells restored sensitivity to Fas-induced apoptosis. These data indicate that oncogenic Ras inhibits basal levels of expression of the fas gene, and although cytokine signal transduction pathways are functional in these cells, the level of surface Fas expression remains below the threshold required for induction of apoptosis. These data identify a mechanism by which Ras-transformed cells may escape from host-mediated immune destruction.