BCL-XL regulates TNF-α-mediated cell death independently of NF-κB, FLIP and IAPs
Issue date
2008Author
Gozzelino, Raffaella
Solé Serra, Carme
Llecha Cano, Núria
Segura Ginard, Miguel Francisco
Moubarak, Rana S.
Iglesias Guimarais, Victoria
Pérez García, María José
Reix, Stéphanie
Zhang, Jisheng
Badiola, Nahuai
Rodríguez Álvarez, José
Trullas, Ramon
Yuste Mateos, Víctor J. (Víctor José)
Comella i Carnicé, Joan Xavier
Suggested citation
Gozzelino, Raffaella;
Solé Serra, Carme;
Llecha Cano, Núria;
Segura Ginard, Miguel Francisco;
Moubarak, Rana S.;
Iglesias Guimarais, Victoria;
...
Comella i Carnicé, Joan Xavier.
(2008)
.
BCL-XL regulates TNF-α-mediated cell death independently of NF-κB, FLIP and IAPs.
Cell Research, 2008, vol. 18, p. 1020–1036.
https://doi.org/10.1038/cr.2008.76.
Metadata
Show full item recordAbstract
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 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.
Is part of
Cell Research, 2008, vol. 18, p. 1020–1036European research projects
Collections
Related items
Showing items related by title, author, creator and subject.
-
The long form of fas apoptotic inhibitory molecule is expressed specifically in neurons and protects them against death receptor-triggered apoptosis
Segura Ginard, Miguel Francisco; Solé Serra, Carme; Pascual, Marta; Moubarak, Rana S.; Pérez García, María José; Gozzelino, Raffaella; Iglesias Guimarais, Victoria; Badiola, Nahuai; Bayascas Ramírez, José Ramón; Llecha Cano, Núria; Rodríguez Álvarez, José; Soriano, Eduardo; Yuste Mateos, Víctor J. (Víctor José); Comella i Carnicé, Joan Xavier (Society for Neuroscience, 2007)Death receptors (DRs) and their ligands are expressed in developing nervous system. However, neurons are generally resistant to death induction through DRs and rather their activation promotes neuronal outgrowth and ... -
FAIM-L Is an IAP-Binding Protein That Inhibits XIAP Ubiquitinylation and Protects from Fas-Induced Apoptosis
Moubarak, Rana S.; Planells Ferrer, Laura; Urresti, Jorge; Reix, Stéphanie; Segura Ginard, Miguel Francisco; Carriba, Paulina; Marqués Fernàndez, Fernando; Solé Serra, Carme; Llecha Cano, Núria; López Soriano, Joaquin; Sanchis, Daniel; Yuste Mateos, Víctor J. (Víctor José); Comella i Carnicé, Joan Xavier (Society for Neuroscience, 2013)The neuronal long isoform of Fas Apoptotic Inhibitory Molecule (FAIM-L) protects from death receptor (DR)-induced apoptosis, yet its mechanism of protection remains unknown. Here, we show that FAIM-L protects rat neuronal ... -
The death receptor antagonist FLIP-L interacts with Trk and is necessary for neurite outgrowth induced by neurotrophins
Moubarak, Rana S.; Solé Serra, Carme; Pascual, Marta; Gutierrez, Humberto; Llovera i Tomàs, Marta; Pérez García, María José; Gozzelino, Raffaella; Segura Ginard, Miguel Francisco; Iglesias Guimarais, Victoria; Reix, Stéphanie; Soler i Tatché, Rosa Ma.; Davies, Alun M.; Soriano, Eduardo; Yuste Mateos, Víctor J. (Víctor José); Comella i Carnicé, Joan Xavier (Society for Neuroscience, 2010)FLICE-inhibitory protein (FLIP) is an endogenous inhibitor of the signaling pathway triggered by the activation of death receptors. Here, we reveal a novel biological function for the long form of FLIP (FLIP-L) in neuronal ...