ORIGINAL ARTICLE

Cell Research (2008): 1020-1036
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www.nature.com/cr

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

Raffaella Gozzelino1, Carme Sole1, Nuria Llecha2, Migue1 F Segura1, Rana S Moubarak3, Victoria Iglesias-Guimarais3, M Jose Perez-Garcia1, Stephanie Reix3,4, Jisheng Zhang1, Nahuai Badiola3,4, Daniel Sanchis1, Jose Rodriguez-Alvarez3,4, Ramon Trullas5, Victor J Yuste3,* and Joan X Comella1,3,4,*

1Cell Signaling and Apoptosis Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Montserrat Roig, 2, 25008 Lleida, Spain;
2Departament de Patologia i Genètica Molecular, Hospital Universitari Arnau de Vilanova, Universitat de Lleida, Montserrat Roig, 2, 25008 Lleida, Spain
3Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra (Edifici M), 08193 Bellaterra, Spain
4Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain;
5Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, CSIC, IDIBAPS, 08036 Barcelona, Spain

Correspondence: Victor J Yuste
Tel: +34-9-35-81-37-62; Fax: +34-9-35-81-15-73
E-mail: victor.yuste@uab.cat

QUpon 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 lentiviral-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-κB-independent manner.

Cell Research (2008) 18:1020–1036. doi: 10.1038/cr.2008.76; published online 1 July 2008

Keywords: apoptosis, Bcl-xL, neuron, NF-κB, PC12, TNF-α

 

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