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FLASH GENE
Symbol CFLAR contributors: mct - updated : 25-10-2015
HGNC name CASP8 and FADD-like apoptosis regulator
HGNC id 1876
Location 2q33.1      Physical location : 201.980.815 - 202.029.001
Synonym name
  • usurpin/FADD-like antiapoptotic molecule 1
  • caspase-like apoptosis regulatory protein
  • inhibitor of FLICE
  • Fas-associated death domain-like interleukin-1beta-converting enzyme
  • c-FLICE inhibitory proteins
  • MACH-related inducer of toxicity
  • FADD-like antiapoptotic molecule 1
  • Synonym symbol(s) c-FLIPR, FLIP, CASPER, FLAME1, MRIT, CASH, CLARP, FLAME, I-FLICE, USURPIN, cFLIP(L), CASP8AP1
    DNA
    TYPE functioning gene
    SPECIAL FEATURE arranged in tandem
    text arranged in tandem with caspase 8 and 10
    STRUCTURE 48.20 kb     10 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    LOC389069 2 similar to selenophosphate synthetase 1 LOC389070 2 LOC389070 FLJ38973 2q33.1 hypothetical protein FLJ38973 FLJ37953 2q33.1 hypothetical protein FLJ37953 FLJ22555 2q33.1 hypothetical protein FLJ22555 DNAPTP6 2q33.2 DNA polymerase-transactivated protein 6 FLJ37818 2q33.2 hypothetical protein FLJ37818 FLJ31322 2q33.2 hypothetical protein FLJ31322 TRIPIN 2q33.2 tripin AOX1 2q33 aldehyde oxidase 1 AOX2 2q33.2 aldehyde oxidase 2 BZW1 2q33 basic leucine zipper and W2 domains 1 LOC391472 2 similar to bA476B13.3 (KIAA0699 protein) CLK1 2q33 CDC-like kinase 1 PPIL3 2q33 peptidylprolyl isomerase (cyclophilin)-like 3 NIF3L1 2q33-q34 NIF3 NGG1 interacting factor 3-like 1 (S. pombe) ORC2L 2q33 origin recognition complex, subunit 2-like (yeast) MGC39518 2q33.2 hypothetical protein MGC39518 NDUFB3 2q31.3 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa CFLAR 2q33 CASP8 and FADD-like apoptosis regulator CASP10 2q33-q34 caspase 10, apoptosis-related cysteine protease CASP8 2q33-q34 caspase 8, apoptosis-related cysteine protease ALS2CR12 2q33.2 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 12 ALS2CR3 2q33 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 3 ALS2CR2 2q33-q34 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 2 FLJ25351 2q33.2 hypothetical protein FLJ25351 ALS2CR4 2q33 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 4 MPP4 2q33.2 membrane protein, palmitoylated 4 (MAGUK p55 subfamily member 4) ALS2 2q33.2 amyotrophic lateral sclerosis 2 (juvenile) LOC151256 2q33.2 hypothetical LOC151256 ALS2CR7 2q33.2 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 7 FZD7 2q33 frizzled homolog 7 (Drosophila) FLJ39061 2q33.2 hypothetical protein FLJ39061 LOC339809 2q33.2 KIAA2012 protein UBL1 2q32.3-q33 ubiquitin-like 1 (sentrin) NOP5/NOP58 2q33.2 ubiquitin-like 1 (sentrin) BMPR2 2q33-q34 bone morphogenetic protein receptor, type II (serine/threonine kinase)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 splicing 2215 55.3 480 - 1998 10200473
    also called usurpin-alpha
    - splicing 1400 52.6 462 - 1998 10200473
    also called usurpin-beta
    - splicing 900 - 292 - 1998 10200473
    also called usurpin-gamma
    10 splicing 2004 55 480 . diminished expression in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells 2011 22190004
  • also called I-FLICE, variant 2 or FLIPL
  • completely abrogated apoptosis (PMID: 18838202)
  • FLIPL and FLIPS exerted differential effects in myeloid leukemic cell lines in response to TRAIL and TNF-alpha (PMID: 18838202)
  • its expression was only marginally modulated by T-cells (PMID: 18509086)
  • inhibits ubiquitylation of beta-catenin and enhances Wnt signaling, and having pathological function in certain cancer cells (PMID: 17573774)
  • FLIPL-silenced cells have a lower rate of proliferation and cell cycle progression when compared to control cells (PMID: 21403465)
  • 6 splicing 1360 - 221 - 2011 22190004
  • also called I-FLICE, variant 3 or FLIPS
  • FLIPL and FLIPS exerted differential effects in myeloid leukemic cell lines in response to TRAIL and TNF-alpha (PMID: 18838202)
  • upon activation, highly induced by T-cells (activation by NFAT contributes to apoptosis resistance of short-term activated T cells) (PMID: 18509086)
  • - splicing 1360 - 442 - 1998 10200473
    also called I-FLICE
    - splicing 1050 - 348 - 1998 10200473
    - splicing 2060 - 445 testis and skeletal muscle predominantly 1997 9228018
    also called FLAME-1-alpha
    - splicing 1060 - 270 - 1997 9228018
    also called FLAME-1-beta
    - splicing 930 - 300 - 1997 9228018
    also called FLAME-1-delta
    - splicing 830 - 221 - 1997 9380701
    also called CLARP2
    - splicing 1400 - 464 - 1997 9228018
    also called FlAME-1-epsilon
    EXPRESSION
    Type widely
    constitutive of
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen    
    Cardiovascularheart   highly
    Digestiveliver    
    Endocrinepancreas   highly
    Nervousbrain    
    Respiratorylung    
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectivebone   
    Epithelialsecretoryglandularendocrine 
    Epithelialsecretoryglandularexocrine 
    Lymphoid    
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text highly in placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal (Fas-associating protein with DEATH domain)
  • FADD-like death effector domain
  • a CALM1-binding region in AAs 197-213
  • a C terminal caspase domain, lacking several amino-acids conserved in cell caspases
  • HOMOLOGY
    interspecies homolog to murine Cflar
    ortholog to Drosophila Cg17493
    homolog to C.elegans Y48g1bm.k
    intraspecies homolog to caspase 8
    Homologene
    FAMILY
  • caspase or peptidase family C14 family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus
    basic FUNCTION
  • regulator apoptosis, functionning as a link between cell survival and cell death pathways in mammalian cells
  • playing a significant role in the regulation of apoptosis in ovarian cancer cells and their sensitivity to cisplatin
  • playing a role in modulation in keratinocytes may not only influence apoptosis sensitivity but may also lead to altered death receptor-dependent skin inflammation
  • playing an essential role in regulation of death receptor-induced apoptosis
  • blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation
  • could either enhance or inhibit apoptosis and lead to NF-kappaB and Erk1/2 activation, and play a role in B cell proliferation and stress MAPK regulation
  • inhibits the apoptosis signaling initiated by death receptor ligation
  • endogenous inhibitor of death receptor-induced apoptosis through the caspase-8 pathway
  • enhances anti-apoptotic AKT1 functions by modulation of GSK3B activity
  • necessary for macrophage differentiation and the homeostatic regulation of granulopoiesis
  • central regulator of cell death in hepatocytes, involving increased activation of caspases and the MAPK JNK (
  • potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors
  • CELLULAR PROCESS cell life, cell death/apoptosis
    cell life, antiapoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • FADD
  • CASP8
  • CASP3
  • TRAF1
  • TRAF2
  • interacting with FOXO3(target of Akt in endothelial cells that can promote apoptosis via CFLAR down-regulation and activation of the extrinsic apoptotic pathway)
  • with TNFSF10
  • interacting with CALM1
  • interaction between MIB1 and CFLAR decreases the association of caspase-8 with CFLAR, which activates caspase-8 and induces cell death
  • interaction between AKT1 and CFLAR
  • PML/RARA binds to FAS and blocks FAS-mediated apoptosis in acute promyelocytic leukemia (APL) by forming an apoptotic inhibitory complex with CFLAR
  • CALM1/CFLAR interaction, with function in regulating Fas-mediated apoptosis and tumorigenesis, which may provide new therapeutic targets for cancer therapy (
  • interacting with SART1, a regulator of CFLAR and drug-induced activation of caspase-8
  • important role for TRAF7 in the activation of JNK following TNF stimulation and clearly point to an involvement of this protein in regulating the turnover of CFLAR and, consequently, cell death
  • interaction between CFLAR and the DNA repair protein XRCC6 that regulates CFLAR protein stability by inhibiting its polyubiquitination
  • TANK, whose expression is increased during osteoclastogenesis, inhibits osteoclast formation, activity and survival, by regulating NFKB1 activity and CFLAR expression
  • cell & other
    REGULATION
    repressed by IL2 after TCR stimulation during progression to the S-phase of the cell cycle
    Other Fas ligand
    its expression is transcriptionally regulated by HNRNPK and nucleolin
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       gain of function
    in inflamed colonic lesions of Crohn's disease
    tumoral     --low  
    in chemoresistant ovarian cancer cells by siRNA increased apoptosis induced by cisplatin
    tumoral     --over  
    associated with prostate cancer progression to the androgen-resistant stage
    constitutional     --low  
    was essential for castration-induced apoptosis in the prostate gland
    tumoral        
    induces apoptosis in a panel of colorectal cancer cell lines in a manner that is dependent on caspase 8 and TNFRSF10B
    tumoral     --over  
    in head and neck squamous cell carcinoma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestiveliver
    biology of CALM1-CFLAR binding may provide new therapeutic targets for cholangiocarcinoma and possibly other cancers
    cancerdigestivecolon
    targeting CFLAR and BIRC4 may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis
    cancerurinary 
    targeting CFLAR, and especially the c-FLIP(L) isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours
    ANIMAL & CELL MODELS
  • mice deficient in Cflar
  • Myeloid specific Flip-deficient mice exhibited growth retardation, premature death, and splenomegaly with altered architecture and extramedullary hematopoiesis