FAIM-L Is an IAP-Binding Protein That Inhibits XIAP Ubiquitinylation and Protects from Fas-Induced Apoptosis

Moubarak, Rana S.; Planells-Ferrer, Laura; Urresti, Jorge; Reix, Stéphanie; Segura, Miguel F.; Carriba, Paulina; Marqués-Fernàndez, Fernando; Solé, Carme; Llecha-Cano, N; López‐Soriano, Joaquín; Sanchı́s, Daniel; Yuste, Vı́ctor J.; Comella, Joan X.

doi:10.1523/jneurosci.2479-13.2013

Cited by 20 publications

(30 citation statements)

References 60 publications

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“…In addition, the validated notch target gene Of the validated genes significantly downregulated by HDACi/AZA treatment in esophageal cancer cells, the anti-apoptotic gene FAIM (rank #4) 62 and MLKL (rank #9) as mediator of selection between necroptosis and apoptosis 63 are of interest because they may influence the observed cell death of esophageal cancer cells. Indeed, this differential regulation of genes associated with apoptosis in non-transformed and malignant cells has been observed before.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Ahrens¹,

Timme

Hoeppner³

et al. 2015

Epigenetics

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Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Ahrens¹,

Timme

Hoeppner³

et al. 2015

Epigenetics

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“…The additional 22 amino acids of FAIM‐L do not contain any recognizable motif, except for the first alanine which acts as an IAP‐binding motif and permits direct interaction with the baculovirus IAP repeat 2 (BIR) domain of the X‐linked inhibitor of apoptosis protein (XIAP) (Moubarak et al . ).…”

Section: Faim1mentioning

confidence: 97%

“…In this context, FAIM‐L binds to XIAP, thus inhibiting its auto‐ubiquitinylation and proteasomal degradation (Moubarak et al . ).…”

Section: Faim1mentioning

confidence: 97%

“…Nuclear magnetic resonance approaches demonstrated that the C-terminal domain of FAIM-S folds as a non-conventional b-sandwich, and the crystal structure of the N-terminal domain revealed a similar conformation containing eight antiparallel b-strands (Li et al 2014). The additional 22 amino acids of FAIM-L do not contain any recognizable motif, except for the first alanine which acts as an IAPbinding motif and permits direct interaction with the baculovirus IAP repeat 2 (BIR) domain of the X-linked inhibitor of apoptosis protein (XIAP) (Moubarak et al 2013).…”

Section: Faim1mentioning

confidence: 99%

“…XIAP is a potent caspase inhibitor that plays a key role in preventing cell death (Eckelman and Salvesen 2006;Srinivasula and Ashwell 2008) and is auto-ubiquitinylated and degraded after an apoptotic stimulus (Yang et al 2000;Jost et al 2009). In this context, FAIM-L binds to XIAP, thus inhibiting its autoubiquitinylation and proteasomal degradation (Moubarak et al 2013).…”

Section: Faim1mentioning

confidence: 99%

See 2 more Smart Citations

Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

Planells-Ferrer

Urresti

Coccia

et al. 2016

Journal of Neurochemistry

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The importance of death receptor (DR) signaling in embryonic development and physiological homeostasis is well established, as is the existence of several molecules that modulate DRs function, among them Fas Apoptotis Inhibitory Molecules. Although FAIM1, FAIM2, and FAIM3 inhibit Fas-induced cell death, they are not structurally related, nor do they share expression patterns. Moreover, they inhibit apoptosis through completely different mechanisms. FAIM1 and FAIM2 protect neurons from DR-induced apoptosis and are involved in neurite outgrowth and neuronal plasticity. FAIM1 inhibits Fas ligand-and tumor necrosis factor alpha-induced apoptosis by direct interaction with Fas receptor and through the stabilization of levels of X-linked inhibitor of apoptosis protein, a potent anti-apoptotic protein that inhibits caspases. Low FAIM1 levels are found in Alzheimer's disease, thus sensitizing neurons to tumor necrosis factor alpha and prompting neuronal loss. FAIM2 protects from Fas by direct interaction with Fas receptor, as well as by modulating calcium release at the endoplasmic reticulum through interaction with Bcl-xL. Several studies prove the role of FAIM2 in diseases of the nervous system, such as ischemia, bacterial meningitis, and neuroblastoma. The less characterized member of the FAIM family is FAIM3, which is expressed in tissues of the digestive and urinary tracts, bone marrow and testes, and restricted to the cerebellum in the nervous system. FAIM3 protects against DR-induced apoptosis by inducing the expression of other DRantagonists such as CFLAR or through the interaction with the DR-adaptor protein Fas-associated via death domain. FAIM3 null mouse models reveal this protein as an important mediator of inflammatory autoimmune responses such as those triggered in autoimmune encephalomyelitis. Given the

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Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina

Sirés

Turch-Anguera

Bogdanov

et al. 2021

J of Neuroscience Research

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Fas Apoptotic Inhibitory Molecule protein (FAIM) is a death receptor antagonist and an apoptosis regulator. It encodes two isoforms, namely FAIM-S (short) and FAIM-L (long), both with significant neuronal functions. FAIM-S, which is ubiquitously expressed, is involved in neurite outgrowth. In contrast, FAIM-L is expressed only in neurons and it protects them from cell death. Interestingly, FAIM-L is downregulated in patients and mouse models of Alzheimer's disease before the onset of neurodegeneration, and Faim transcript levels are decreased in mouse models of retinal degeneration. However, few studies have addressed the role of FAIM in the central nervous system, yet alone the retina. The retina is a highly specialized tissue, and its degeneration has proved to precede pathological mechanisms of neurodegenerative diseases. Here we describe that Faim depletion in mice damages the retina persistently and leads to late-onset photoreceptor death in older mice. Immunohistochemical analyses showed that Faim knockout (Faim −/− ) mice present ubiquitinated aggregates throughout the retina from early ages. Moreover, retinal cells released stress signals that can signal to Müller cells, as shown by immunofluorescence and qRT-PCR.Müller cells monitor retinal homeostasis and trigger a gliotic response in Faim −/− mice that becomes pathogenic when sustained. In this regard, we observed pronounced vascular leakage at later ages, which may be caused by persistent inflammation.These results suggest that FAIM is an important player in the maintenance of retinal homeostasis, and they support the premise that FAIM is a plausible early marker for late photoreceptor and neuronal degeneration.

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FAIM-L Is an IAP-Binding Protein That Inhibits XIAP Ubiquitinylation and Protects from Fas-Induced Apoptosis

Cited by 20 publications

References 60 publications

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina

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