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

Sole C, Dolcet X, Segura MF, Gutierrez H, Diaz-Meco MT, Gozzelino R, Sanchis D, Bayascas JR, Gallego C, Moscat J, Davies AM, Comella JX - J. Cell Biol. (2004)

Bottom Line: 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.The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras-ERK pathway.These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras-ERK pathway and NF-kappa B.

View Article: PubMed Central - PubMed

Affiliation: Group Cell Signalling and Apoptosis, Department of Basic Medical Sciences, Universitat de Lleida, 25008 Lleida, Spain.

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-kappa B activation, and blocking this activation by using a super-repressor I kappa B alpha or by carrying out experiments using cortical neurons from mice that lack the p65 NF-kappa B 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-kappa B.

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FAIM increases NGF-induced neurite outgrowth. (A) Phase-contrast micrographs of PC12 cells stably transfected with empty vector (top), FAIM-S (middle), or FAIM-L (bottom). PC12 cells treated with complete medium (left) or with NGF 100 ng/ml (right) for 1 d. Bar, 100 μm. (B) Histogram showing the neurite length measurements of cells shown in A. Significant differences in neurite length between Neo and FAIM-S are indicated (*, P < 0.001; t test).
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fig2: FAIM increases NGF-induced neurite outgrowth. (A) Phase-contrast micrographs of PC12 cells stably transfected with empty vector (top), FAIM-S (middle), or FAIM-L (bottom). PC12 cells treated with complete medium (left) or with NGF 100 ng/ml (right) for 1 d. Bar, 100 μm. (B) Histogram showing the neurite length measurements of cells shown in A. Significant differences in neurite length between Neo and FAIM-S are indicated (*, P < 0.001; t test).

Mentions: Despite the absence of an antiapoptotic function in PC12 cells and SCG neurons, we noticed that when these cells were transfected with FAIM and maintained in presence of NGF, there was a marked increase in neurite outgrowth compared with empty vector-transfected neurons. To ascertain if FAIM was able to modulate NGF-induced neurite outgrowth or influence neurite growth independently of NGF, pools of PC12 cells stably transfected with FAIM or the empty vector were grown with or without NGF for 1 d. Fig. 2 shows that in NGF-supplemented medium, PC12 cells overexpressing FAIM exhibited a fivefold increase in neurite length compared with control-transfected cells. However, overexpression of FAIM did not have any effect on neurite outgrowth from PC12 cells grown in complete medium without NGF. These results suggest that FAIM is able to regulate neurite outgrowth in NGF-differentiated PC12 cells. When the long form of FAIM was tested in the same assay, no enhanced neurite outgrowth was observed (Fig. 2) and, therefore, the studies using this splicing variant were no longer pursued.


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

Sole C, Dolcet X, Segura MF, Gutierrez H, Diaz-Meco MT, Gozzelino R, Sanchis D, Bayascas JR, Gallego C, Moscat J, Davies AM, Comella JX - J. Cell Biol. (2004)

FAIM increases NGF-induced neurite outgrowth. (A) Phase-contrast micrographs of PC12 cells stably transfected with empty vector (top), FAIM-S (middle), or FAIM-L (bottom). PC12 cells treated with complete medium (left) or with NGF 100 ng/ml (right) for 1 d. Bar, 100 μm. (B) Histogram showing the neurite length measurements of cells shown in A. Significant differences in neurite length between Neo and FAIM-S are indicated (*, P < 0.001; t test).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172486&req=5

fig2: FAIM increases NGF-induced neurite outgrowth. (A) Phase-contrast micrographs of PC12 cells stably transfected with empty vector (top), FAIM-S (middle), or FAIM-L (bottom). PC12 cells treated with complete medium (left) or with NGF 100 ng/ml (right) for 1 d. Bar, 100 μm. (B) Histogram showing the neurite length measurements of cells shown in A. Significant differences in neurite length between Neo and FAIM-S are indicated (*, P < 0.001; t test).
Mentions: Despite the absence of an antiapoptotic function in PC12 cells and SCG neurons, we noticed that when these cells were transfected with FAIM and maintained in presence of NGF, there was a marked increase in neurite outgrowth compared with empty vector-transfected neurons. To ascertain if FAIM was able to modulate NGF-induced neurite outgrowth or influence neurite growth independently of NGF, pools of PC12 cells stably transfected with FAIM or the empty vector were grown with or without NGF for 1 d. Fig. 2 shows that in NGF-supplemented medium, PC12 cells overexpressing FAIM exhibited a fivefold increase in neurite length compared with control-transfected cells. However, overexpression of FAIM did not have any effect on neurite outgrowth from PC12 cells grown in complete medium without NGF. These results suggest that FAIM is able to regulate neurite outgrowth in NGF-differentiated PC12 cells. When the long form of FAIM was tested in the same assay, no enhanced neurite outgrowth was observed (Fig. 2) and, therefore, the studies using this splicing variant were no longer pursued.

Bottom Line: 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.The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras-ERK pathway.These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras-ERK pathway and NF-kappa B.

View Article: PubMed Central - PubMed

Affiliation: Group Cell Signalling and Apoptosis, Department of Basic Medical Sciences, Universitat de Lleida, 25008 Lleida, Spain.

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-kappa B activation, and blocking this activation by using a super-repressor I kappa B alpha or by carrying out experiments using cortical neurons from mice that lack the p65 NF-kappa B 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-kappa B.

Show MeSH
Related in: MedlinePlus