Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis
Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis
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DOI：
10.1016/s0960-9822(99)80454-0
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发表时间：
1999-09-23
期刊：
影响因子：
9.2
通讯作者：
Downward, J
中科院分区：
文献类型：
--
作者：
Rytömaa, M;Martins, LM;Downward, J
大多数未转化的贴壁细胞从细胞外基质脱离会促进细胞凋亡，这一过程称为失巢凋亡[1,2]。尽管 ras 癌基因的粘附或转化已被证明可以通过激活磷脂酰肌醇 3-激酶和蛋白激酶 B (PKB/Akt) 来保护上皮细胞免于凋亡，但该过程中涉及的死亡信号传导机制尚不清楚 [3]。在这里，我们发现，在许多未转化的上皮细胞系中，FAS 相关死亡结构域蛋白 (FADD) 的显性失活形式的表达可阻断脱离诱导的细胞凋亡 (失巢凋亡)。由于死亡受体 CD95、DR4 和 DR5 的可溶性胞外结构域未能阻断失巢凋亡，因此我们得出结论，这些死亡受体的配体依赖性激活不参与该过程。分离诱导 caspase 8 和 caspase 3 的强烈激活。分离诱导的 caspase-8 激活不需要下游 caspase 的功能，但会被抗凋亡蛋白 Bcl-2 或 Bcl-X-L 的过度表达所阻断。我们认为 caspase-8 激活是失巢凋亡的起始事件，随后发生涉及线粒体事件的正反馈循环。
Detachment of most untransformed adherent cells from the extracellular matrix promotes apoptosis, in a process termed anoikis [1,2]. The death signalling mechanisms involved in this process are not known, although adhesion or transformation by ras oncogenes have been shown to protect epithelial cells from apoptosis through activation of phosphatidylinositol 3-kinase and protein kinase B (PKB/Akt) [3]. Here we show that detachment-induced apoptosis (anoikis) is blocked by the expression of a dominant-negative form of FAS-associated death domain protein (FADD) in a number of untransformed epithelial cell lines. Because the soluble extracellular domains of the death receptors CD95, DR4 and DR5 failed to block anoikis, we conclude that ligand-dependent activation of these death receptors is not involved in this process. Detachment induced strong activation of caspase 8 and caspase 3. Detachment-induced caspase-8 activation did not require the function of downstream caspases but was blocked by overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-X-L. We propose that caspase-8 activation is the initiating event in anoikis, which is subsequently subject to a positive-feedback loop involving mitochondrial events.