Volume 18, No 10, Oct 2008

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 18 Issue 10, October 2008: 1020-1036

ORIGINAL ARTICLES

BCL-X_L 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 Reix^3,4, Jisheng Zhang¹, Nahuai Badiola^3,4, Daniel Sanchis¹, Jose Rodriguez-Alvarez^3,4, Ramon Trullas⁵, Victor J Yuste^3,* and Joan X Comella^1,3,4,*

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(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-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-κB 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-κB-independent manner.

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

FULL TEXT | PDF

Browse 1731