The death receptor antagonist FAIM promotes neurite outgrowth by a mechanism that depends on ERK and NF-κB signaling

Abstract

Fas apoptosis inhibitory molecule (FAIM) is a protein identified as an antagonist of Fas-induced cell death. We show that FAIM overexpression fails to rescue neurons from trophic factor deprivation, but exerts a marked neurite growth–promoting action in different neuronal systems. Whereas FAIM overexpression greatly enhanced neurite outgrowth from PC12 cells and sympathetic neurons grown with nerve growth factor (NGF), reduction of endogenous FAIM levels by RNAi decreased neurite outgrowth in these cells. FAIM overexpression promoted NF-κB activation, and blocking this activation by using a super-repressor IκBα or by carrying out experiments using cortical neurons from mice that lack the p65 NF-κB subunit prevented FAIM-induced neurite outgrowth. The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras–ERK pathway. Finally, we show that FAIM interacts with both Trk and p75 neurotrophin receptor NGF receptors in a ligand-dependent manner. These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras–ERK pathway and NF-κB.

Genetic deletion of faim reveals its role in modulating c-FLIP expression during CD95-mediated apoptosis of lymphocytes and hepatocytes

“…As FAIM was highly expressed in spleen and thymus, 7,8 we characterized B-and T-cell development in faim À/À mice. Flow cytometry analyses revealed that mutant mice had normal B and T lymphopoiesis ( Figure 2).…”

“…FAIM is expressed in neurons and has been shown to regulate neurite outgrowth 8 and neuronal survival. 9 It is possible that FAIM could play a more critical role in the nervous system and we are currently assessing its involvement in Parkinson's and Alzheimer's diseases where massive neuronal cell death is known to occur.…”

“…FAIM is highly conserved in evolution and widely expressed in all tissues although it bears no homology to other known proteins. 7 Although most tissues express the short isoform of the protein (FAIM-S), neuronal cells express both FAIM-S and a long isoform, FAIM-L. 8 FAIM-S was shown to promote neurite outgrowth through a mechanism involving NF-kB and Ras-ERK activation, 8 whereas FAIM-L was demonstrated to protect neurons from cell death in response to Fas and TNFR1 engagement. 9 Apart from its role in protecting B-lymphocytes and neuronal cells from death receptor-induced apoptosis, 7,9 FAIM was also shown to improve the survival of HEK-293 cells in serum-free media 10 and CHO cells in fed-batch cultures.…”

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

“…PC12 cells stably transfected with IκBα super-repressor (SR-IκBα)-pcDNA3 or empty-pcDNA3 vectors were obtained as described by Sole et al [45]. For RNAi experiments, constructs were generated in pSUPER.retro.puro (OligoEngine, Seattle, WA) using specific oligonucleotides targeting Bcl-x L , c-FLIP or cIAP2 sequences as follows: shBcl-x L GAT TGC AAG TTG GAT GGC C; shFLIP-F.1 GGT TCC GAT CAG TTG AAT T; shFLIP-F.2 CAC CTT GTT TCC GAT TAT A; shXIAP-X.1 AGA ATC CTA TGG TGC AAG A; shXIAP-X.2 GGT GCA AGA AGC TAT ACG; shIAP2-I2.1 CAC GGA GAA GGC CAG ATT A and shIAP2-I2.2 GTT CGT TGG CCA AGT TCA A.…”

“…To determine NF-κB status (RelA/p65 nuclear translocation and NF-κB activity) experiments were performed as described previously [45].…”