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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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Protein alignments of FAIM. (A) Comparison of FAIM protein sequences from rat, mouse, human, C. elegans, D. melanogaster, G. Gallus, and D. rerio. Identical amino acids are shaded in black, and those with conservative changes in gray. The additional 22 amino acids of the long form are underlined. Some protein sequences are available from GenBank/EMBL/DDBJ under accession no. NP_543171(rat FAIM-S), AAL77007 (rat FAIM-L), NP_035940 (mouse FAIM-S), NP_060617 (human FAIM-S). The remaining sequence data were predicted from nucleotide sequences BE986872 (mouse FAIM-L), BQ638715 (5′ human FAIM-L), BU323531 (G. gallus), the combination of BG304437, AL923876 (D. rerio), AF003387 (C. elegans), and NM_137164 (D. melanogaster). (B) Semi-quantitative RT-PCR quantification of FAIM-S and FAIM-L expression in different rat tissues (top) and in P1 mouse SCG neurons, E15 mouse cortical neurons, and PC12 cells (bottom). As controls of the amplification GAPDH and L27 ribosomal proteins were used. C(−), control PCR reactions without reverse transcriptase; M, 50-bp DNA ladder marker.
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fig1: Protein alignments of FAIM. (A) Comparison of FAIM protein sequences from rat, mouse, human, C. elegans, D. melanogaster, G. Gallus, and D. rerio. Identical amino acids are shaded in black, and those with conservative changes in gray. The additional 22 amino acids of the long form are underlined. Some protein sequences are available from GenBank/EMBL/DDBJ under accession no. NP_543171(rat FAIM-S), AAL77007 (rat FAIM-L), NP_035940 (mouse FAIM-S), NP_060617 (human FAIM-S). The remaining sequence data were predicted from nucleotide sequences BE986872 (mouse FAIM-L), BQ638715 (5′ human FAIM-L), BU323531 (G. gallus), the combination of BG304437, AL923876 (D. rerio), AF003387 (C. elegans), and NM_137164 (D. melanogaster). (B) Semi-quantitative RT-PCR quantification of FAIM-S and FAIM-L expression in different rat tissues (top) and in P1 mouse SCG neurons, E15 mouse cortical neurons, and PC12 cells (bottom). As controls of the amplification GAPDH and L27 ribosomal proteins were used. C(−), control PCR reactions without reverse transcriptase; M, 50-bp DNA ladder marker.

Mentions: FAIM is a newly identified antiapoptotic protein that is highly conserved among multiple animal phyla and is expressed in at least two isoforms, long and short (Schneider et al., 1999, Zhong et al., 2001). By searching publicly available EST databases (GenBank, NCBI, and NIH), we found clones encoding both the short and the long forms of rat FAIM. Fig. 1 A compares the FAIM sequences from Rattus norvegicus with Drosophila melanogaster, C. elegans, Gallus gallus, Danio rerio, Mus musculus, and Homo sapiens. The cloned rat sequences are available from GenBank/EMBL/DDBJ under accession no. NP_543171 (short form) and AAL77007 (long form). Alignment of FAIM vertebrate sequences shows more than 68% of homology. The percentage of homology is reduced to 30–50% when vertebrate sequences were aligned with D. melanogaster and C. elegans FAIM sequences, respectively (Table I).


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)

Protein alignments of FAIM. (A) Comparison of FAIM protein sequences from rat, mouse, human, C. elegans, D. melanogaster, G. Gallus, and D. rerio. Identical amino acids are shaded in black, and those with conservative changes in gray. The additional 22 amino acids of the long form are underlined. Some protein sequences are available from GenBank/EMBL/DDBJ under accession no. NP_543171(rat FAIM-S), AAL77007 (rat FAIM-L), NP_035940 (mouse FAIM-S), NP_060617 (human FAIM-S). The remaining sequence data were predicted from nucleotide sequences BE986872 (mouse FAIM-L), BQ638715 (5′ human FAIM-L), BU323531 (G. gallus), the combination of BG304437, AL923876 (D. rerio), AF003387 (C. elegans), and NM_137164 (D. melanogaster). (B) Semi-quantitative RT-PCR quantification of FAIM-S and FAIM-L expression in different rat tissues (top) and in P1 mouse SCG neurons, E15 mouse cortical neurons, and PC12 cells (bottom). As controls of the amplification GAPDH and L27 ribosomal proteins were used. C(−), control PCR reactions without reverse transcriptase; M, 50-bp DNA ladder marker.
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Related In: Results  -  Collection

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fig1: Protein alignments of FAIM. (A) Comparison of FAIM protein sequences from rat, mouse, human, C. elegans, D. melanogaster, G. Gallus, and D. rerio. Identical amino acids are shaded in black, and those with conservative changes in gray. The additional 22 amino acids of the long form are underlined. Some protein sequences are available from GenBank/EMBL/DDBJ under accession no. NP_543171(rat FAIM-S), AAL77007 (rat FAIM-L), NP_035940 (mouse FAIM-S), NP_060617 (human FAIM-S). The remaining sequence data were predicted from nucleotide sequences BE986872 (mouse FAIM-L), BQ638715 (5′ human FAIM-L), BU323531 (G. gallus), the combination of BG304437, AL923876 (D. rerio), AF003387 (C. elegans), and NM_137164 (D. melanogaster). (B) Semi-quantitative RT-PCR quantification of FAIM-S and FAIM-L expression in different rat tissues (top) and in P1 mouse SCG neurons, E15 mouse cortical neurons, and PC12 cells (bottom). As controls of the amplification GAPDH and L27 ribosomal proteins were used. C(−), control PCR reactions without reverse transcriptase; M, 50-bp DNA ladder marker.
Mentions: FAIM is a newly identified antiapoptotic protein that is highly conserved among multiple animal phyla and is expressed in at least two isoforms, long and short (Schneider et al., 1999, Zhong et al., 2001). By searching publicly available EST databases (GenBank, NCBI, and NIH), we found clones encoding both the short and the long forms of rat FAIM. Fig. 1 A compares the FAIM sequences from Rattus norvegicus with Drosophila melanogaster, C. elegans, Gallus gallus, Danio rerio, Mus musculus, and Homo sapiens. The cloned rat sequences are available from GenBank/EMBL/DDBJ under accession no. NP_543171 (short form) and AAL77007 (long form). Alignment of FAIM vertebrate sequences shows more than 68% of homology. The percentage of homology is reduced to 30–50% when vertebrate sequences were aligned with D. melanogaster and C. elegans FAIM sequences, respectively (Table I).

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