BCL-XL regulates TNF-α-mediated cell death independently of NF-кB,FLIP and IAPs

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2008,（10）
• 页码范围: 1020-1036
• 页数: 17页
• 语种: 英文
• DOI: 10.1038/cr.2008.76

摘要

Upon activation,tumor necrosis factor alpha (TNF-α) receptor can engage apoptotic or survival pathways.Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death.It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB.Nevertheless,such evidence has remained elusive in the nervous system.Here,we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons.However,cells treated with Actinomycin D (ActD) become susceptible to TNF-α-induced cell death through the activation of caspase-8,generation of tBid and activation of caspase-9 and -3.Analysis of several proteins involved in TNF-α receptor signaling showed no significant downregulation of NF-κB target genes,such as IAPs or FLIP,under such conditions.However,Bcl-xL protein levels,but not those of Bcl-2,Bax and Bak,are reduced by ActD or TNF-α/ActD treatments.Moreover,Bcl-xL overexpression fully protects cells against TNF-α/ActD-induced cell death.When endogenous levels of Bcl-XL are specifically downregulated by ientiviral-based RNAi,cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis.Furthermore,Bcl-xL downregulation does not affect TNF-α-mediated NF-κB activation.Altogether,our results demonstrate that Bcl-xL,and not Bcl-2,FLIP or IAPs,acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-KB-independent manner.