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

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dc.contributor.authorGozzelino, Raffaella
dc.contributor.authorSolé Serra, Carme
dc.contributor.authorLlecha Cano, Núria
dc.contributor.authorSegura Ginard, Miguel Francisco
dc.contributor.authorMoubarak, Rana S.
dc.contributor.authorIglesias Guimarais, Victoria
dc.contributor.authorPérez García, María José
dc.contributor.authorReix, Stéphanie
dc.contributor.authorZhang, Jisheng
dc.contributor.authorBadiola, Nahuai
dc.contributor.authorSanchis, Daniel
dc.contributor.authorRodríguez Álvarez, José
dc.contributor.authorTrullas, Ramon
dc.contributor.authorYuste Mateos, Víctor J. (Víctor José)
dc.contributor.authorComella i Carnicé, Joan Xavier
dc.date.accessioned2016-12-02T09:44:38Z
dc.date.embargoEndDate2025-01-01
dc.date.issued2008
dc.description.abstractUpon 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.ca_ES
dc.description.sponsorshipThis work was funded by Spanish Government “Ministerio de Sanidad y Consumo” (Redes Temáticas de Investigación Cooperativa and CIBERNED), Spanish Government “Ministerio de Educación y Ciencia” (SAF2007-60287) and Generalitat de Catalunya (Suport als Grups de Recerca Consolidats) to JXC, and by grants from “Ministerio de Educación y Ciencia” SAF2005-05106 (to JR-A) and SAF2005-02197 (to DS). RG and VI-G hold postgraduate fellowships from the DURSI (Generalitat de Catalunya) and Fons Social Europeu. CS and MFS were supported by postgraduate fellowships from the Spanish Government, MEC and FIS, respectively. RSM is under a postdoctoral contract associated with the SAF2007-60287 grant. SR is supported by a postdoctoral contract from the CIBERNED. JZ holds a fellowship from “Ministerio de Educación y Ciencia”. NB is a recipient of a fellowship from the “Gobierno Vasco”. DS is under the Ramon y Cajal Program from the “Ministerio de Educación y Ciencia” (Spain). VJY was supported by a Beatriu de Pinós contract from Generalitat de Catalunya and is presently under the 2006 Ramon y Cajal Program from the “Ministerio de Educación y Ciencia” (Spain), co-financed by the European Social Fund.ca_ES
dc.identifier.doihttps://doi.org/10.1038/cr.2008.76
dc.identifier.idgrec013551
dc.identifier.issn1001-0602
dc.identifier.urihttp://hdl.handle.net/10459.1/58761
dc.language.isoengca_ES
dc.publisherSpringer Natureca_ES
dc.relationMIECI/PN2004-2007/SAF2007-60287
dc.relationMIECI/PN2004-2007/SAF2005-05106
dc.relationMIECI/PN2004-2007/SAF2005-02197
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1038/cr.2008.76ca_ES
dc.relation.ispartofCell Research, 2008, vol. 18, p. 1020–1036ca_ES
dc.rights(c) Shanghai Institutes for Biological Sciences, 2008ca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_ES
dc.subjectApoptosisca_ES
dc.subjectBcl-xLca_ES
dc.subjectNeuronca_ES
dc.subjectNF-κBca_ES
dc.titleBCL-XL regulates TNF-α-mediated cell death independently of NF-κB, FLIP and IAPsca_ES
dc.typearticleca_ES
dc.type.versionpublishedVersionca_ES
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