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CFLAR (CASP8 and FADD-like apoptosis regulator)

Identity

Other namesCASH
CASP8AP1
CLARP
Casper
FLAME
FLAME-1
FLAME1
FLIP
I-FLICE
MRIT
USURPIN
c-FLIP
c-FLIPL
c-FLIPR
c-FLIPS
HGNC (Hugo) CFLAR
LocusID (NCBI) 8837
Location 2q33.1
Location_base_pair Starts at 201983269 and ends at 202037411 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  Genomic Organization and splice variants of c-FLAR (c-FLIP) gene. Schematic representation of the structure of the 48kb c-FLAR gene, which contains 14 exons and is transcribed into 11 alternative splice forms. The start and stop sites for translation of the various splice forms are indicated as arrowheads and asterisks, respectively. Only 3 proteins are expressed at the protein level: FLIPS, FLIPR and FLIPL (adapted from Djerbi M et al 2001).
Description 14 exons; DNA Size 48kb.
Transcription FLIPL: mRNA Size: 2243 nucleotides (nt); coding sequence: 1443 nt; FLIPS: mRNA size: 1062 nt; coding sequence: 666 nt.

Protein

Note In 1997, a new family of viral genes encoding viral FLIP (v-FLIP, Fas-associated death domain (FADD)-like interleukin-1 beta converting enzyme (FLICE) inhibitory protein) were identified as proteins containing the Death Effector Domain (DED) which interact with certain caspases: caspase 8 (also termed FLICE) and caspase 10 (Hofmann, 1999). These proteins are principally composed of two homologous DED regions, which are found in a wide family of DED-containing proteins, including procaspase-8, procaspase-10 and FADD, which are components of the DISC (Death Inducing Signalling Complex) formed by death receptors such as Fas (CD95), DR4 (TRAIL-R1) and DR5 (TRAIL-R2) (Ashkenazi and Dixit, 1999). The v-FLIP proteins were first identified in gamma-herpesviruses, such as the Kaposi-associated human herpesvirus-8 (HHV-8), the equine herpesvirus-2 (EHV-2), the herpesvirus saimiri (HVS) and found in the rhesus rhadinovirus (RRV) (Bertin et al., 1997; Hu et al., 1997; Searles et al., 1999; Thome et al., 1997). Two additional v-FLIP variants with carboxy-terminal extensions of unknown function are found in the human molluscipoxvirus (MCV) (Bertin et al., 1997; Hu et al., 1997; Thome et al., 1997).
Soon after the discovery of v-FLIP proteins, the mammalian cellular counterparts were identified, and called c-FLIP proteins (also called CASH, Casper, CLARP, FLAME, I-FLICE, MRIT or usurpin). Among 13 distinct c-FLIP splice variants which have been reported, only three are expressed as proteins: the 55 kDa long form (c-FLIPL), the 26 kDa short form (c-FLIPS) and the 24 kDa short form of c-FLIP (c-FLIPR), identified in the Raji B-cell line (Golks et al., 2005; Budd et al., 2006).
 
  Overview of c-FLIP isoforms and v-FLIP isoforms. All the c-FLIP proteins carry two tandem death effector domains (DEDs). c-FLIPL also contains a caspase 8-like domain. The sites cleaved by procaspase-8 or by active caspase-8 are shown. Total number of amino acids is given.
Description c-FLIPL is composed of 480 amino acids and contains a longer carboxy-terminus than cFLIPS. c-FLIPL closely resembles the overall structure of procaspase-8 and procaspase-10 (Figure 2). c-FLIPL contains two DEDs followed by a caspase-like domain. However, the C-terminal caspase-like domain of c-FLIPL lacks caspase enzymatic activity, owing to the substitution of several amino acids, including the crucial cysteine residue in the Gln-Ala-Cys-X-Gly motif (X: any amino acid) and the histidine residue in the His-Gly motif (Cohen, 1997). These two residues are necessary for caspase catalytic activity and are conserved in all caspases. c-FLIPL contains two conserved aspartic-acid cleavage sites: Asp-198, between DED2 and the p20-like domain; and Asp-376, between the p20- and p10-like domains, both of which can be cleaved during Fas- and TRAIL-induced apoptosis (Irmler, 1997; Scaffidi et al., 1999; Golks et al., 2006). This leads to the generation of p43-FLIP, which is implicated in the activation of different signalling pathways such as NF-kappa B pathway (Kataoka and Tschopp, 2004). In addition to NF-kappaB signaling, c-FLIPL has also been shown to activate Erk signaling pathway by binding to Raf-1 (Kataoka, 2000; Park et al., 2001).

The short form c-FLIPS is composed of 221 amino acids and has the same structure as vFLIP proteins, except that in addition to the two DEDs of cFLIPS, a carboxy-terminal tail composed of approximatively 20 amino acids is present that seems to be crucial for its ubiquitinylation and subsequent proteasomal degradation (Poukkula et al., 2005).

The short form c-FLIPR is composed of 213 amino acids, contains two DEDs and lacks the additional carboxy terminal amino acids present in c-FLIPS (Golks et al., 2005).

 
  Schematic diagram of c-FLIP recruitment to the DISC. All the c-FLIP proteins carry two tandem death effector domains (DEDs), which can bind FADD and procaspase-8. c-FLIPL is structurally very similar to procaspase-8 apart from the active site of c-FLIP in which cysteine 360 has been substituted by a tyrosine, and in another active site, histidine 317 has been substituted by an arginine in c-FLIPL.
Expression c-FLIPL is expressed in many tissues, most abundantly in the heart, skeletal muscle, lymphoid tissues and kidney. c-FLIP is abundantly and constitutively expressed in a wide array of normal cell types, including neurons, cardiac myocytes, endothelial cells, keratinocytes, pancreatic beta cells, dendritic cells (DCs), macrophages, CD34+ haematopoietic stem cells and spermatocytes (Ashany et al., 1999; Bouchet, 2002; Davidson et al., 2003; Desbarats, 2003; Giampietri, 2003; Kiener, 1997; Kim et al., 2002; Maedler, 2002; Marconi, 2004; Rescigno, 2000). c-FLIP is highly expressed in various types of tumour cells, including colorectal carcinoma (Ryu et al., 2001; Ullenhag et al., 2007), gastric carcinoma (Nam et al., 2003; Zhou et al., 2004), pancreatic carcinoma (Elnemr et al., 2001), Hodgkin's lymphoma (Dutton et al., 2004; Mathas et al., 2004; Thomas et al., 2002), B cell chronic lymphocytic leukemia (MacFarlane et al., 2002; Olsson et al., 2001), melanoma (Griffith et al., 1998), ovarian carcinoma (Abedini et al., 2004; Mezzanzanica et al., 2004), cervical carcinoma (Wang et al., 2007), bladder urothelial carcinoma and prostate carcinoma (Korkolopoulou et al., 2004; Zhang et al., 2004). All of these tumours are often resistant to death receptor-mediated apoptosis. The expression of c-FLIP has been proven to be one of the major determinants of the resistance to death ligands such as FasL and TRAIL (TNF-related apoptosis-inducing ligand), and numerous reports have shown that down-regulation of c-FLIP results in sensitizing various resistant tumour cells to death ligands (Kim et al., 2000; Longley et al., 2006; Ricci et al., 2004; Wilson et al., 2007).
Localisation c-FLIP proteins are localized in the cytosol.
Function In many studies, in vitro, FLIP proteins (v-FLIP, c-FLIPR, c-FLIPS and c-FLIPL) protect cells against apoptosis induced by several death receptors, including FAS, tumour-necrosis factor (TNF) receptor 1 ( TNFR1 ), TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (TRAILR1; also known as DR4), TRAILR2 (also known as DR5) and TNFR-related apoptosis-mediating protein ( TRAMP; also known as DR3). Due to its high structural homology with procaspase-8, FLIP interferes with caspase-8 activation at the death-inducing signalling complex (DISC), which is formed after death receptor ligation (Ashkenazi and Dixit, 1999). The inhibition of Death Receptor-mediated apoptosis by FLIP is due to competition between the DEDs of FLIP and procaspase-8/10 for recruitment to the adaptor protein FADD at the DISC (Irmler, 1997; Srinivasula, 1997). Procaspase-8 recruitment to the DISC results in its homodimerization and two sequential cleavage steps that generate p10 and p18 fragments that heterodimerize to form fully active (p10-p18)2 caspase-8 that dissociates from the DISC (Krammer et al., 2007).

When the death receptors are stimulated by their corresponding ligand, they recruit the adapter molecule FADD. FADD can then recruit DED containing proteins, e.g. caspase-8, and form a DISC. c-FLIP inhibits caspase-8 activation at the DISC. c-FLIPL and c-FLIPS have been shown to block death receptor-mediated apoptosis by forming a proteolytically inactive heterodimer with procaspase-8 (Golks et al., 2005; Krueger et al., 2001). However, cleavage is blocked at different stages. For c-FLIPS and c-FLIPR, both cleavage steps required for procaspase-8 activation are completely blocked. In contrast, c-FLIPL allows partial cleavage of procaspase-8 at the DISC (Figure 3). When a molecule of procaspase-8 and c-FLIPL come into contact at the DISC, a conformational change in the two molecules occurs. This leads to the autocatalytic cleavage of the p10 subunit from procaspase-8. c-FLIPL is also partially cleaved by the procaspase-8 molecule to generate a p12 subunit. However, cleavage is stopped at this stage and no p18 subunit is generated from caspase-8. It has been hypothesised that the second reciprocal trans-catalytic cleavage step cannot occur because of the lack of the cysteine residue at the active site of c-FLIPL (Micheau, 2002). The resulting cleavage products are p41/43- and p10-caspase-8 products; and p43- and p12-c-FLIPL intermediates. Furthermore, Kreuger et al demonstrated that the p41/43-caspase-8 and p43-c-FLIPL intermediates remain bound at the DISC (Krueger et al., 2001). Recently, it has been proposed that the DISC-bound caspase 8/FLIP complex has catalytic activity that is not capable of generating a pro-apoptotic signal, but that can cleave local substrates such as RIP (receptor-interacting protein) (Micheau, 2002).

Implicated in

Entity Hodgkin's lymphoma (cHD)
Note Classical Hodgkin's lymphoma (cHL), a common human lymphoma, has been proposed to be derived from germinal centre (GC) B cells in the majority of cases (Kuppers et al., 2002). Among tumour-forming cells, the malignant Hodgkin/Reed-Sternberg (HRS) cells, which represents the malignant population of cHD disease, are rare and represent only 1% of cells in affected lymph nodes. HRS cells have lost their B cell phenotype, including immunoglobulin (Ig) expression (Schwering et al., 2003). Usually, B cells with non-functional Ig expression undergo apoptosis.
Disease Hodgkin/Reed-Sternberg (HRS) cells are most often resistant to Death receptor-mediated apoptosis such as is mediated by FasL or TRAIL. The expression of c-FLIP has been proven to be one of the major determinants of this resistance. HRS cells have been shown to overexpress c-FLIP proteins in a NF-kappa B-dependent manner. Some studies have shown that the high level of c-FLIP prevent the activation of caspase-8 by inhibition of procaspase-8 processing. To remove this resistance to Death receptor mediated apoptosis, some reports have shown that specific down-regulation of c-FLIP by small interfering RNA oligoribonucleotides strategies is sufficient to sensitize HRS cells to Fas and TRAIL-induced apoptosis (Mathas et al., 2004).
  
Entity Colorectal cancer (CRC)
Note Colorectal cancer is a major cause of cancer mortality. Response rates in the advanced disease setting are of the order of 45% to 50% for the most effective drug combinations. Drug resistance is a major problem in this disease (and other cancers) and is often the result of insufficient apoptosis induced by chemotherapy.
Disease Clinical studies have demonstrated significantly elevated c-FLIP expression in colorectal tumours (Ryu et al., 2001), suggesting that c-FLIP may be play a role in the pathogenesis of this disease. Indeed, c-FLIP(L) overexpression was associated with poor prognosis in colorectal cancer patients (Ullenhag et al., 2007).
  
Entity Graves' disease
Note Graves' disease is an autoimmune form of hyperthyroidism. In the context of this disease, lymphocyte TH2 cells infiltrate the thyroid gland and, via production of IL4 and IL10, stimulate thyrocytes to become more resistant to Fas-mediated apoptosis, in part by upregulation of c-FLIP and Bcl-XL (Stassi, 2000).
  
Entity Multiple sclerosis (MS)
Note Multiple sclerosis (MS): a neuroinflammatory disease that is thought to have an autoimmune basis due to autoreactive T cells responding to myelin self-antigens (Conlon et al., 1999). Autoimmune diseases such as MS can result from the lack of elimination of pathogenic, autoreactive lymphocytes.
Disease In this disease, the pathological upregulation of FLIP levels in T cells might contribute to the accumulation of lymphocytes in cortical-spinal-fluid and accumulation of activated-peripheral T cells in patients with clinically active MS. FLIPL and FLIPS were found to be specifically overexpressed in T cells of MS patients, indicating that abnormally high FLIP expression levels might extend the viability of potentially pathogenic, autoreactive T cells in the context of this disease (Semra et al., 2001; Sharief, 2000).
  

External links

Nomenclature
HGNC (Hugo)CFLAR   1876
Cards
AtlasCFLARID40065ch2q33
Entrez_Gene (NCBI)CFLAR  8837  CASP8 and FADD-like apoptosis regulator
GeneCards (Weizmann)CFLAR
Ensembl (Hinxton)ENSG00000003402 [Gene_View]  chr2:201983269-202037411 [Contig_View]  CFLAR [Vega]
ICGC DataPortalENSG00000003402
cBioPortalCFLAR
AceView (NCBI)CFLAR
Genatlas (Paris)CFLAR
WikiGenes8837
SOURCE (Princeton)NM_001127183 NM_001127184 NM_001202515 NM_001202516 NM_001202517 NM_001202518 NM_001202519 NM_003879
Genomic and cartography
GoldenPath (UCSC)CFLAR  -  2q33.1   chr2:201983269-202037411 +  2q33-q34   [Description]    (hg19-Feb_2009)
EnsemblCFLAR - 2q33-q34 [CytoView]
Mapping of homologs : NCBICFLAR [Mapview]
OMIM603599   
Gene and transcription
Genbank (Entrez)AB209600 AF005774 AF005775 AF009616 AF009617
RefSeq transcript (Entrez)NM_001127183 NM_001127184 NM_001202515 NM_001202516 NM_001202517 NM_001202518 NM_001202519 NM_003879
RefSeq genomic (Entrez)AC_000134 NC_000002 NC_018913 NG_029005 NT_005403 NW_001838863 NW_004929305
Consensus coding sequences : CCDS (NCBI)CFLAR
Cluster EST : UnigeneHs.731912 [ NCBI ]
CGAP (NCI)Hs.731912
Alternative Splicing : Fast-db (Paris)GSHG0017103
Alternative Splicing GalleryENSG00000003402
Gene ExpressionCFLAR [ NCBI-GEO ]     CFLAR [ SEEK ]   CFLAR [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO15519 (Uniprot)
NextProtO15519  [Medical]
With graphics : InterProO15519
Splice isoforms : SwissVarO15519 (Swissvar)
Domaine pattern : Prosite (Expaxy)CASPASE_P20 (PS50208)    DED (PS50168)   
Domains : Interpro (EBI)DEATH-like_dom [organisation]   DED [organisation]   Pept_C14_caspase [organisation]   Pept_C14_ICE_p20 [organisation]   Pept_C14A_p45_core [organisation]  
Related proteins : CluSTrO15519
Domain families : Pfam (Sanger)DED (PF01335)    Peptidase_C14 (PF00656)   
Domain families : Pfam (NCBI)pfam01335    pfam00656   
Domain families : Smart (EMBL)CASc (SM00115)  DED (SM00031)  
DMDM Disease mutations8837
Blocks (Seattle)O15519
PDB (SRS)3H11    3H13   
PDB (PDBSum)3H11    3H13   
PDB (IMB)3H11    3H13   
PDB (RSDB)3H11    3H13   
Human Protein AtlasENSG00000003402 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO15519
HPRD04671
IPIIPI00007287   IPI00219239   IPI00394836   IPI00219241   IPI00219242   IPI00219243   IPI00216956   IPI00216957   IPI00978912   IPI00216959   IPI00216960   IPI00414806   IPI00216962   IPI00216963   IPI00953066   IPI00216958   IPI00556163   IPI00927572   IPI00952600   IPI00925124   IPI00924478   IPI00927333   
Protein Interaction databases
DIP (DOE-UCLA)O15519
IntAct (EBI)O15519
FunCoupENSG00000003402
BioGRIDCFLAR
InParanoidO15519
Interologous Interaction database O15519
IntegromeDBCFLAR
STRING (EMBL)CFLAR
Ontologies - Pathways
Ontology : AmiGOprotease binding  cysteine-type endopeptidase activity  protein binding  cytoplasm  cytosol  proteolysis  apoptotic process  apoptotic process  skeletal muscle tissue development  enzyme activator activity  skeletal muscle atrophy  regulation of satellite cell proliferation  skeletal myofibril assembly  modulation by virus of host morphology or physiology  death-inducing signaling complex  negative regulation of apoptotic process  positive regulation of catalytic activity  positive regulation of I-kappaB kinase/NF-kappaB cascade  skeletal muscle tissue regeneration  positive regulation of NF-kappaB transcription factor activity  regulation of necroptotic process  apoptotic signaling pathway  ripoptosome  negative regulation of myoblast fusion  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of extrinsic apoptotic signaling pathway  negative regulation of extrinsic apoptotic signaling pathway  regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Ontology : EGO-EBIprotease binding  cysteine-type endopeptidase activity  protein binding  cytoplasm  cytosol  proteolysis  apoptotic process  apoptotic process  skeletal muscle tissue development  enzyme activator activity  skeletal muscle atrophy  regulation of satellite cell proliferation  skeletal myofibril assembly  modulation by virus of host morphology or physiology  death-inducing signaling complex  negative regulation of apoptotic process  positive regulation of catalytic activity  positive regulation of I-kappaB kinase/NF-kappaB cascade  skeletal muscle tissue regeneration  positive regulation of NF-kappaB transcription factor activity  regulation of necroptotic process  apoptotic signaling pathway  ripoptosome  negative regulation of myoblast fusion  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of extrinsic apoptotic signaling pathway  negative regulation of extrinsic apoptotic signaling pathway  regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Pathways : BIOCARTAFAS signaling pathway ( CD95 ) [Genes]    Induction of apoptosis through DR3 and DR4/5 Death Receptors [Genes]    HIV-I Nef: negative effector of Fas and TNF [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]   
Pathways : KEGGNF-kappa B signaling pathway    Apoptosis    TNF signaling pathway    Chagas disease (American trypanosomiasis)   
Protein Interaction DatabaseCFLAR
Wikipedia pathwaysCFLAR
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)CFLAR
snp3D : Map Gene to Disease8837
SNP (GeneSNP Utah)CFLAR
SNP : HGBaseCFLAR
Genetic variants : HAPMAPCFLAR
Exome VariantCFLAR
1000_GenomesCFLAR 
ICGC programENSG00000003402 
Somatic Mutations in Cancer : COSMICCFLAR 
CONAN: Copy Number AnalysisCFLAR 
Mutations and Diseases : HGMDCFLAR
Genomic VariantsCFLAR  CFLAR [DGVbeta]
dbVarCFLAR
ClinVarCFLAR
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM603599   
MedgenCFLAR
GENETestsCFLAR
Disease Genetic AssociationCFLAR
Huge Navigator CFLAR [HugePedia]  CFLAR [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneCFLAR
Homology/Alignments : Family Browser (UCSC)CFLAR
Phylogenetic Trees/Animal Genes : TreeFamCFLAR
Chemical/Protein Interactions : CTD8837
Chemical/Pharm GKB GenePA26425
Clinical trialCFLAR
Cancer Resource (Charite)ENSG00000003402
Other databases
Probes
Litterature
PubMed278 Pubmed reference(s) in Entrez
CoreMineCFLAR
iHOPCFLAR

Bibliography

Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis.
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J Biol Chem. 1997 Apr 11;272(15):9621-4.
PMID 9092488
 
Inhibition of death receptor signals by cellular FLIP.
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J.
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FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis.
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Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors.
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Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells.
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J Immunol. 1998 Sep 15;161(6):2833-40.
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Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway.
Ashany D, Savir A, Bhardwaj N, Elkon KB.
J Immunol. 1999 Nov 15;163(10):5303-11.
PMID 10553053
 
Apoptosis control by death and decoy receptors.
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J Immunol. 1999 Nov 15;163(10):5303-11.
PMID 10209153
 
The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system.
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PMID 10408805
 
The modular nature of apoptotic signalling proteins.
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Cell Mol Life Sci. 1999 Jul;55(8-9):1113-28. (Review).
PMID 10442092
 
The role of c-FLIP in modulation of CD95-induced apoptosis.
Scaffidi C, Schmitz I, Krammer PH, Peter ME.
J Biol Chem. 1999 Jan 15;274(3):1541-8.
PMID 9880531
 
Sequence and genomic analysis of a Rhesus macaque rhadinovirus with similarity to Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8.
Searles RP, Bergquam EP, Axthelm MK, Wong SW.
J Virol. 1999 Apr;73(4):3040-53.
PMID 10074154
 
The caspase-8 inhibitor FLIP promotes activation of NF-[kappa]B and Erk signalling pathways.
Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J.
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PMID 10837247
 
Molecular determinants of response to TRAIL in killing of normal and cancer cells.
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PMID 10690508
 
Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1[beta], and the production of interferon-[gamma] in the absence of IL-12 during DC-T cell cognate interaction. A new role for fas ligand in inflammatory responses.
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J Exp Med. 2000 Dec 4;192(11):1661-8.
PMID 11104808
 
Increased cellular expression of the caspase inhibitor FLIP in intrathecal lymphocytes from patients with multiple sclerosis.
Sharief MK.
J Neuroimmunol. 2000 Nov 1;111(1-2):203-9.
PMID 11063839
 
Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins.
Stassi G, Di Liberto D, Todaro M, Zeuner A, Ricci-Vitiani L, Stoppacciaro A, Ruco L, Farina F, Zummo G, De Maria R.
Nat Immunol. 2000 Dec;1(6):483-8.
PMID 11101869
 
Characterization of the human FLICE-inhibitory protein locus and comparison of the anti-apoptotic activity of four different flip isoforms.
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PMID 11439165
 
Human pancreatic cancer cells disable function of Fas receptors at several levels in Fas signal transduction pathway.
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PMID 11172597
 
Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signalling complex.
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J Biol Chem. 2001 Jun 8;276(23):20633-40.
PMID 11279218
 
Sensitization to TRAIL-induced apoptosis and modulation of FLICE-inhibitory protein in B chronic lymphocytic leukemia by actinomycin D.
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PMID 11753607
 
Alternative splicing variants of c-FLIP transduce the differential signal through the Raf or TRAF2 in TNF-induced cell proliferation.
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Biochem Biophys Res Commun. 2001 Dec 21;289(5):1205-10.
PMID 11741321
 
Increased expression of cFLIP(L) in colonic adenocarcinoma.
Ryu BK, Lee MG, Chi SG, Kim YW, Park JH.
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PMID 11329136
 
Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis.
Semra YK, Seidi OA, Sharief MK.
J Neuroimmunol. 2001 Feb 15;113(2):268-74.
PMID 11164911
 
Differential sensitivity of endothelial cells of various species to apoptosis induced by gene transfer of Fas ligand: role of FLIP levels.
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Mol Med. 2002 Oct;8(10):612-23.
PMID 12477972
 
Human CD34+ hematopoietic stem/progenitor cells express high levels of FLIP and are resistant to Fas-mediated apoptosis.
Kim H, Whartenby KA, Georgantas RW 3rd, Wingard J, Civin CI.
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PMID 11897874
 
Biology of Hodgkin's lymphoma.
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Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia.
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PMID 12360407
 
FLIP switches Fas-mediated glucose signalling in human pancreatic [beta] cells from apoptosis to cell replication.
Maedler K, Fontana A, Ris F, Sergeev P, Toso C, Oberholzer J, Lehmann R, Bachmann F, Tasinato A, Spinas GA, Halban PA, Donath MY.
Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8236-41.
PMID 12060768
 
The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signalling complex.
Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW, Briand C, Grutter MG.
J Biol Chem. 2002 Nov 22;277(47):45162-71.
PMID 12215447
 
Constitutive expression of c-FLIP in Hodgkin and Reed-Sternberg cells.
Thomas RK, Kallenborn A, Wickenhauser C, Schultze JL, Draube A, Vockerodt M, Re D, Diehl V, Wolf J.
Am J Pathol. 2002 Apr;160(4):1521-8.
PMID 11943736
 
FLIP protects cardiomyocytes from apoptosis induced by simulated ischemia/reoxygenation, as demonstrated by short hairpin-induced (shRNA) silencing of FLIP mRNA.
Davidson SM, Stephanou A, Latchman DS.
J Mol Cell Cardiol. 2003 Nov;35(11):1359-64.
PMID 14596792
 
Fas engagement induces neurite growth through ERK activation and p35 upregulation.
Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme JS, Newell MK.
Nat Cell Biol. 2003 Feb;5(2):118-25.
PMID 12545171
 
FLIP is expressed in mouse testis and protects germ cells from apoptosis.
Giampietri C, Petrungaro S, Coluccia P, D'Alessio A, Starace D, Riccioli A, Padula F, Srinivasula SM, Alnemri E, Palombi F, Filippini A, Ziparo E, De Cesaris P.
Cell Death Differ. 2003 Feb;10(2):175-84.
PMID 12700645
 
5-fluorouracil: mechanisms of action and clinical strategies.
Longley DB, Harkin DP, Johnston PG.
Nat Rev Cancer. 2003 May;3(5):330-8. (Review).
PMID 12724731
 
Upregulation of FLIP(S) by Akt, a possible inhibition mechanism of TRAIL-induced apoptosis in human gastric cancers.
Nam SY, Jung GA, Hur GC, Chung HY, Kim WH, Seol DW, Lee BL.
Cancer Sci. 2003 Dec;94(12):1066-73.
PMID 14662022
 
Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.
Schwering I, Brauninger A, Klein U, Jungnickel B, Tinguely M, Diehl V, Hansmann ML, Dalla-Favera R, Rajewsky K, Kuppers R.
Blood. 2003 Feb 15;101(4):1505-12.
PMID 12393731
 
Possible role of FLICE-like inhibitory protein (FLIP) in chemoresistant ovarian cancer cells in vitro.
Abedini MR, Qiu Q, Yan X, Tsang BK.
Oncogene. 2004 Sep 16;23(42):6997-7004.
PMID 15258564
 
Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin's lymphoma cells from autonomous Fas-mediated death.
Dutton A, O'Neil JD, Milner AE, Reynolds GM, Starczynski J, Crocker J, Young LS, Murray PG.
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6611-6.
PMID 15096587
 
N-terminal fragment of c-FLIPL processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-[kappa]B signalling pathway.
Kataoka T, Tschopp J.
Mol Cell Biol. 2004 Apr;24(7):2627-36.
PMID 15024054
 
c-FLIP expression in bladder urothelial carcinomas: its role in resistance to Fas-mediated apoptosis and clinicopathologic correlations.
Korkolopoulou P, Goudopoulou A, Voutsinas G, Thomas-Tsagli E, Kapralos P, Patsouris E, Saetta AA.
Urology. 2004 Jun;63(6):1198-204.
PMID 15183989
 
FLICE/caspase-8 activation triggers anoikis induced by [beta]1-integrin blockade in human keratinocytes.
Marconi A, Atzei P, Panza C, Fila C, Tiberio R, Truzzi F, Wachter T, Leverkus M, Pincelli C.
J Cell Sci. 2004 Nov 15;117(Pt 24):5815-23.
PMID 15507484
 
c-FLIP mediates resistance of Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis.
Mathas S, Lietz A, Anagnostopoulos I, Hummel F, Wiesner B, Janz M, Jundt F, Hirsch B, Johrens-Leder K, Vornlocher HP, Bommert K, Stein H, Dorken B.
J Exp Med. 2004 Apr 19;199(8):1041-52.
PMID 15078899
 
CD95-mediated apoptosis is impaired at receptor level by cellular FLICE-inhibitory protein (long form) in wild-type p53 human ovarian carcinoma.
Mezzanzanica D, Balladore E, Turatti F, Luison E, Alberti P, Bagnoli M, Figini M, Mazzoni A, Raspagliesi F, Oggionni M, Pilotti S, Canevari S.
Clin Cancer Res. 2004 Aug 1;10(15):5202-14.
PMID 15297424
 
Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity.
Ricci MS, Jin Z, Dews M, Yu D, Thomas-Tikhonenko A, Dicker DT, El-Deiry WS.
Mol Cell Biol. 2004 Oct;24(19):8541-55.
PMID 15367674
 
Persistent c-FLIP(L) expression is necessary and sufficient to maintain resistance to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in prostate cancer.
Zhang X, Jin TG, Yang H, DeWolf WC, Khosravi-Far R, Olumi AF.
Cancer Res. 2004 Oct 1;64(19):7086-91.
PMID 15466204
 
Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma.
Zhou XD, Yu JP, Liu J, Luo HS, Chen HX, Yu HG.
Clin Sci (Lond). 2004 Apr;106(4):397-405.
PMID 14636156
 
c-FLIPR, a new regulator of death receptor-induced apoptosis.
Golks A, Brenner D, Fritsch C, Krammer PH, Lavrik IN.
J Biol Chem. 2005 Apr 15;280(15):14507-13.
PMID 15701649
 
Rapid turnover of c-FLIPshort is determined by its unique C-terminal tail.
Poukkula M, Kaunisto A, Hietakangas V, Denessiouk K, Katajamaki T, Johnson MS, Sistonen L, Eriksson JE.
J Biol Chem. 2005 Jul 22;280(29):27345-55.
PMID 15886205
 
cFLIP regulation of lymphocyte activation and development.
Budd RC, Yeh WC, Tschopp J.
Nat Rev Immunol. 2006 Mar;6(3):196-204.
PMID 16498450
 
c-FLIP inhibits chemotherapy-induced colorectal cancer cell death.
Longley DB, Wilson TR, McEwan M, Allen WL, McDermott U, Galligan L, Johnston PG.
Oncogene. 2006 Feb 9;25(6):838-48.
PMID 16247474
 
Life and death in peripheral T cells.
Krammer PH, Arnold R, Lavrik IN.
Nat Rev Immunol. 2007 Jul;7(7):532-42.
PMID 17589543
 
Cellular FLICE-inhibitory protein regulates chemotherapy-induced apoptosis in breast cancer cells.
Rogers KM, Thomas M, Galligan L, Wilson TR, Allen WL, Sakai H, Johnston PG, Longley DB.
Mol Cancer Ther. 2007 May;6(5):1544-51.
PMID 17513603
 
Overexpression of FLIPL is an independent marker of poor prognosis in colorectal cancer patients.
Ullenhag GJ, Mukherjee A, Watson NF, Al-Attar AH, Scholefield JH, Durrant LG.
Clin Cancer Res. 2007 Sep 1;13(17):5070-5.
PMID 17785559
 
The relationship between c-FLIP expression and human papillomavirus E2 gene disruption in cervical carcinogenesis.
Wang W, Wang S, Song X, Sima N, Xu X, Luo A, Chen G, Deng D, Xu Q, Meng L, Lu Y, Ma D.
Gynecol Oncol. 2007 Jun;105(3):571-7.
PMID 17433827
 
c-FLIP: a key regulator of colorectal cancer cell death.
Wilson TR, McLaughlin KM, McEwan M, Sakai H, Rogers KM, Redmond KM, Johnston PG, Longley DB.
Cancer Res. 2007 Jun 15;67(12):5754-62.
PMID 17575142
 
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Written09-2008Christophe Le Clorennec, Daniel B Longley, Timothy Wilson
Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland

Citation

This paper should be referenced as such :
Le, Clorennec C ; Longley, DB ; Wilson, T
CFLAR (CASP8 and FADD-like apoptosis regulator)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(8):549-555.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/CFLARID40065ch2q33.html

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