TNFα induces survival through the FLIP-L-dependent activation of the MAPK/ERK pathway

F. Marques-Fernandez, L. Planells-Ferrer, R. Gozzelino, K. M.O. Galenkamp, S. Reix, N. Llecha-Cano, J. Lopez-Soriano, V. J. Yuste, R. S. Moubarak, J. X. Comella

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44 Citations (Scopus)

Abstract

Activation of tumor necrosis factor receptor-1 can trigger survival or apoptosis pathways. In many cellular models, including the neuronal cell model PC12, it has been demonstrated that inhibition of protein synthesis is sufficient to render cells sensitive to apoptosis induced by TNFα. The survival effect is linked to the translocation of the transcription factor nuclear factor-kappa B (NF-κB) to the nucleus and activation of survival-related genes such as FLICE-like inhibitory protein long form (FLIP-L) or IAPs. Nonetheless, we previously reported an NF-κB-independent contribution of Bcl-xL to cell survival after TNFα treatment. Here, we demonstrate that NF-κB-induced increase in FLIP-L expression levels is essential for mitogen-activated protein kinases/ extracellular signal-regulated kinases (MAPK/ERK) activation. We demonstrate that FLIP-L behaves as a Raf-1 activator through both proteinprotein interaction and Raf-1 kinase activation, without the requirement of the classical Ras activation. Importantly, prevention of FLIP-L increase by NF-κB inhibition or knockdown of endogenous FLIP-L blocks MAPK/ERK activation after TNFα treatment. From a functional point of view, we show that inhibition of the MAPK/ERK pathway and the NF-κB pathway are equally relevant to render PC12 cells sensitive to cell death induced by TNFα. Apoptosis induced by TNFα under these conditions is dependent on jun nuclear kinase1/2 JNK1/2-dependent Bim upregulation. Therefore, we report a previously undescribed and essential role for MAPK/ERK activation by FLIP-L in the decision between cell survival and apoptosis upon TNFα stimulation. © 2013 Macmillan Publishers Limited All rights reserved.
Original languageEnglish
JournalCell Death and Disease
Volume4
DOIs
Publication statusPublished - 1 Feb 2013

Keywords

  • Apoptosis
  • ERK/MAPK
  • FLIP-L
  • NF-κB
  • TNFα

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