TY - JOUR
T1 - BCL-X L regulates TNF-α-mediated cell death independently of NF-kB, FLIP and IAPs
AU - Gozzelino, Raffaella
AU - Sole, Carme
AU - Llecha, Nuria
AU - Segura, Miguel F.
AU - Moubarak, Rana S.
AU - Iglesias-Guimarais, Victoria
AU - Perez-Garcia, M. Jose
AU - Reix, Stephanie
AU - Zhang, Jisheng
AU - Badiola, Nahuai
AU - Sanchis, Daniel
AU - Rodriguez-Alvarez, Jose
AU - Trullas, Ramon
AU - Yuste, Victor J.
AU - Comella, Joan X.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Bcl-xL
KW - Neuron
KW - NF-?B
KW - PC12
KW - TNF-α
U2 - 10.1038/cr.2008.76
DO - 10.1038/cr.2008.76
M3 - Article
VL - 18
SP - 1020
EP - 1036
JO - Cell Research
JF - Cell Research
SN - 1001-0602
IS - 10
ER -