BCL-X L regulates TNF-α-mediated cell death independently of NF-kB, FLIP and IAPs

Raffaella Gozzelino, Carme Sole, Nuria Llecha, Miguel F. Segura, Rana S. Moubarak, Victoria Iglesias-Guimarais, M. Jose Perez-Garcia, Stephanie Reix, Jisheng Zhang, Nahuai Badiola, Daniel Sanchis, Jose Rodriguez-Alvarez, Ramon Trullas, Victor J. Yuste, Joan X. Comella

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27 Citations (Scopus)

Abstract

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-B. 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-B target genes, such as IAPs or FLIP, under such conditions. However, Bcl-x L protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-α/ActD treatments. Moreover, Bcl-x L overexpression fully protects cells against TNF-α/ActD-induced cell death. When endogenous levels of Bcl-x L are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis. Furthermore, Bcl-x L downregulation does not affect TNF-α-mediated NF-B activation. Altogether, our results demonstrate that Bcl-x L, and not Bcl-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-B-independent manner. © 2008 IBCB, SIBS, CAS All rights reserved.
Original languageEnglish
Pages (from-to)1020-1036
JournalCell Research
Volume18
Issue number10
DOIs
Publication statusPublished - 1 Jan 2008

Keywords

  • Apoptosis
  • Bcl-xL
  • Neuron
  • NF-?B
  • PC12
  • TNF-α

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    Gozzelino, R., Sole, C., Llecha, N., Segura, M. F., Moubarak, R. S., Iglesias-Guimarais, V., Perez-Garcia, M. J., Reix, S., Zhang, J., Badiola, N., Sanchis, D., Rodriguez-Alvarez, J., Trullas, R., Yuste, V. J., & Comella, J. X. (2008). BCL-X L regulates TNF-α-mediated cell death independently of NF-kB, FLIP and IAPs. Cell Research, 18(10), 1020-1036. https://doi.org/10.1038/cr.2008.76