The Long Form of Fas Apoptotic Inhibitory Molecule Is Expressed Specifically in Neurons and Protects Them against Death Receptor-Triggered Apoptosis

Segura, Miguel F.; Solé, Carme; Pascual, Marta; Moubarak, Rana S.; Pérez-García, M. Jose; Gozzelino, Raffaella; Iglesias, Victoria; Badiola, Nahuai; Bayascas, José R.; Llecha, Nuria; Rodríguez‐Álvarez, José; Soriano, Eduardo; Yuste, Vı́ctor J.; Comella, Joan X.

doi:10.1523/jneurosci.3462-07.2007

Cited by 69 publications

(92 citation statements)

References 63 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Notably in the nervous system, recent advances have been made concerning the role of FAIM and Lifeguard (FAIM2) in the antagonism of apoptosis induced by FasL or tumor necrosis factor ␣ (TNF␣) (Sole et al, 2004;Fernández et al, 2007;Segura et al, 2007). Particularly, we have demonstrated that the two splice variants of FAIM [the long form of FAIM (FAIM-L) and FAIM-S] display diverse functions in the nervous system.…”

Section: Discussionmentioning

confidence: 99%

The Death Receptor Antagonist FLIP-L Interacts with Trk and Is Necessary for Neurite Outgrowth Induced by Neurotrophins

Moubarak

Solé²,

Pascual³

et al. 2010

J. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

The Death Receptor Antagonist FLIP-L Interacts with Trk and Is Necessary for Neurite Outgrowth Induced by Neurotrophins

Moubarak

Solé²,

Pascual³

et al. 2010

J. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The proteins were separated on the SDS-PAGE and transferred to the filter by standard procedures. The filters were probed with antibodies to FAIM L kindly provided by Prof. J. Comella (Segura et al, 2007) and reprobed with antibodies to ␣-actin (Sigma). Thirteen-day-old mouse dopaminergic neurons were plated at similar density and grown with 100 ng/ml GDNF or 50 ng/ml BDNF for 5 d. Neurotrophic factors were then removed (GDNFϪ, BDNFϪ) or not removed (GDNFϩ, BDNFϩ) for 3 d in the presence or absence of caspase inhibitor BAF (50 M).…”

Section: Cultures Of 13-d-old Mouse Ventral Mesencephalon and Survivamentioning

confidence: 99%

Death Receptors and Caspases But Not Mitochondria Are Activated in the GDNF- or BDNF-Deprived Dopaminergic Neurons

Saarma²,

Arumäe³

2008

J. Neurosci.

View full text Add to dashboard Cite

Neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), promote survival of midbrain dopaminergic neurons, but the death pathways activated in the dopaminergic neurons by deprivation of these factors are poorly studied. We show here that deprivation of GDNF or BDNF triggers a novel mitochondria-independent death pathway in the cultured embryonic dopaminergic neurons: cytochrome c was not released from the mitochondria to cytosol, proapoptotic protein Bax was not activated, and overexpressed Bcl-xL did not block the death. Caspases were critically required, because the death was completely blocked by caspase inhibitor BAF [boc-aspartyl(OMe)-fluoromethylketone] and overexpression of dominant-negative mutants of caspase-9, -3, and -7 significantly blocked the death. Also, the death receptor pathway was involved, because blockage of caspase-8 or FADD (Fas-associated protein with death domain), an adapter required for caspase-8 activation, inhibited death induced by GDNF or BDNF deprivation. Ligation of Fas by agonistic anti-Fas antibody induced apoptosis in the GDNF-or BDNF-maintained neurons, and inhibition of Fas by Fas-Fc chimera blocked the death of GDNF-or BDNF-deprived neurons, whereas FAIM L (long isoform of Fas apoptosis inhibitory molecule) could control the activity of Fas in the dopaminergic neurons.

show abstract

“…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. The ability of FAIM to induce neurite outgrowth in addition to its ability to enhance neuronal survival also render it as an ideal therapeutic target for these diseases.…”

Section: Discussionmentioning

confidence: 99%

“…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. 11 This suggests a potential application of FAIM in biotechnology through its role in enhancing the longevity of cell lines used for the production of biologics.…”

mentioning

confidence: 99%

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

Huo

et al. 2009

Cell Death Differ

View full text Add to dashboard Cite

Fas-apoptosis inhibitory molecule (FAIM) is inducibly expressed in B lymphocytes and had been shown to antagonize Fas-mediated killing of B-cell lines in vitro. However, its mechanism and role in vivo are unknown. We have generated faim À/À mice and found these mutants to be viable. In contrast to fas À/À mice, faim À/À mice have normal B-and T-cell populations. However, faim À/À B cells and thymocytes show increased sensitivity to Fas-triggered apoptosis in vitro, and faim À/À mice suffer greater mortality and exhibit exacerbated liver damage in response to Fas (CD95) engagement in vivo. The lack of FAIM results in greater activation of caspase-8 and -3 in Fas-stimulated thymocytes. CD95 or Fas (APO-1/TNFRSF6) is a member of the tumor necrosis factor (TNF) receptor superfamily and is capable of inducing apoptosis in a variety of cell-types. 1,2 The physiological ligand for Fas is CD178 (FasL), which is expressed mainly by activated T cells. 3 In mice, mutation in fas (lpr mice) or fasl (gld mice) leads to lymphoproliferation, the accumulation of abnormal lymphocytes, autoantibody production, and this ultimately results in systemic autoimmunity. 3,4 Thus, Fasmediated apoptosis is critical for regulating the function and homeostasis of lymphocytes.Fas-signaling is triggered upon the binding of FasL, which leads to the trimerization of Fas and the formation of the downstream death-inducing signaling complex (DISC) that comprises the cytosolic adapter protein FADD and procaspase-8. 5 Procaspase-8 undergoes auto-cleavage to generate active caspase-8, which in turn leads to the activation of caspase-3 and execution of apoptosis. As apoptosis plays an important role in physiology, its activation process must be tightly regulated. Hence, other than activators, negative regulators of Fas-signaling also exist. One of these inhibitors of Fas-mediated apoptosis is the cellular FLICE-inhibitory protein (c-FLIP) which is known to antagonize Fas-signaling by interfering with the recruitment of procaspase-8 to the DISC. 6 Fas-apoptosis inhibitory molecule (FAIM) was also cloned as an inducibly expressed, anti-apoptotic protein that antagonized Fas-triggered cell death of B-cell lines in vitro. 7 However, its mode of action is unknown. 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. 11 This suggests a potential application of FAIM in biotechnology through its role in e...

show abstract

The Long Form of Fas Apoptotic Inhibitory Molecule Is Expressed Specifically in Neurons and Protects Them against Death Receptor-Triggered Apoptosis

Cited by 69 publications

References 63 publications

The Death Receptor Antagonist FLIP-L Interacts with Trk and Is Necessary for Neurite Outgrowth Induced by Neurotrophins

The Death Receptor Antagonist FLIP-L Interacts with Trk and Is Necessary for Neurite Outgrowth Induced by Neurotrophins

Death Receptors and Caspases But Not Mitochondria Are Activated in the GDNF- or BDNF-Deprived Dopaminergic Neurons

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

Contact Info

Product

Resources

About