Wang R, Zhang L, Yin D, Mufson R A, Shi Y
Department of Immunology, Jerome H. Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
J Immunol. 1998 Sep 1;161(5):2201-7.
Fas (CD95/APO-1) is a transmembrane protein of the TNF/neuron growth factor receptor family. Ligation of Fas by specific Abs or Fas ligand (FasL/CD95 ligand) induces rapid apoptotic cell death in a variety of cell types. Despite progress in understanding the death signals transduced from Fas, very little is known with regard to the mechanisms by which Fas expression is regulated. Using our previously established murine T cell hybridoma model A1.1, we show that specific protein kinase C (PKC) inhibitors could block activation-induced Fas expression and apoptosis. The activation of PKC with PMA or 1-oleoyl-2-acetyl-sn-glycerol could mimic the TCR signal by inducing the expression of Fas but not FasL. PKC-dependent Fas expression was also observed in several murine and human tumor cell lines. Since the inhibition of Ca2+ redistribution by an inhibitor of intracellular Ca2+ mobilization, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride, inhibited TCR-induced FasL but not Fas, the expression of Fas appears to be independent of Ca2+ mobilization. Significantly, expression of the newly identified Fas-regulatory gene, TDAG51, was found to be dependent upon the activity of PKC. PKC activation only induced Fas expression in cells expressing wild-type TDAG51. Thus, Fas expression is likely mediated by PKC through TDAG51.
Fas（CD95/APO-1）是肿瘤坏死因子/神经生长因子受体家族的一种跨膜蛋白。特异性抗体或Fas配体（FasL/CD95配体）与Fas结合可诱导多种细胞类型迅速发生凋亡性细胞死亡。尽管在理解从Fas转导的死亡信号方面取得了进展，但对于Fas表达的调控机制却知之甚少。利用我们先前建立的小鼠T细胞杂交瘤模型A1.1，我们发现特异性蛋白激酶C（PKC）抑制剂可阻断激活诱导的Fas表达和凋亡。用佛波酯或1-油酰-2-乙酰-sn-甘油激活PKC可通过诱导Fas而非FasL的表达来模拟TCR信号。在几种小鼠和人类肿瘤细胞系中也观察到了PKC依赖性的Fas表达。由于细胞内Ca2+动员抑制剂8-（二乙氨基）-辛基-3,4,5-三甲氧基苯甲酸盐酸盐对Ca2+再分布的抑制作用抑制了TCR诱导的FasL而非Fas，Fas的表达似乎独立于Ca2+动员。值得注意的是，发现新鉴定的Fas调节基因TDAG51的表达依赖于PKC的活性。PKC激活仅在表达野生型TDAG51的细胞中诱导Fas表达。因此，Fas表达可能由PKC通过TDAG51介导。
