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FLASH GENE
Symbol CFLAR contributors: mct - updated : 16-10-2024
HGNC name CASP8 and FADD-like apoptosis regulator
HGNC id 1876
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a N terminal (Fas-associating protein with DEATH domain)
  • FADD-like death effector domain
  • DED 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,cytosolic
    intracellular,nucleus
    text
  • could translocate into the nucleus and might be involved in the Wnt signaling pathway
    • 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
  • inhibitor of death receptor-mediated apoptosis that is up-regulated in a variety of cancers, contributing to apoptosis resistance
  • mechanistically, CFLAR controls a broad transcriptional program, partially by NFKB1 activation
  • in addition to its anti-apoptotic function, CFLAR is also an important mediator of tumor growth
  • PRMT1-mediated methylation of CFLAR plays a critical role in hepatic lipid metabolism
    • 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
  • RBM5, a close homologue of RBM10, regulates alternative splicing of apoptosis-related genes, FAS and CFLAR
  • FADD regulates NFKB1 activation and promotes ubiquitination of CFLAR to induce apoptosis
  • CASP8/CFLAR heterodimer implicated in control of inflammatory cytokines during microbial infection
  • CFLAR -associated protein RUVBL1, which is a nuclear protein identified as a cofactor in the transcriptional regulation of CTNNB1
  • CASP8 is required upstream of both CFLAR and CASP10 and death-inducing signaling complex (DISC) formation critically depends on the scaffold function of CASP8
  • is a central regulator of CASP8-mediated apoptosis and necroptosis
  • PRMT5 and PRMT1 mediate the distinct effects on CFLARL degradation by regulating the binding of E3 ligase ITCH in lung cancer cells
  • positively regulates autophagy, by enhancing BECN1 protein stability
  • BCLAF1 exerts its anti-apoptotic function by promoting the transcription of CFLAR, a caspase 8 antagonist, downstream of NFKB1 activation
  • USP27X is a novel regulator of CFLAP protein expression and a deubiquitinase in fine tuning death receptor signalling pathways to execute apoptosis
  • CFLAR-BCAR1 association is mediated by the DED domain of CFLAR and the SD domain of BCAR1
  • PRMT1 was observed to interact with and methylate CFLAR, ultimately leading to its ubiquitination-mediated protein degradation
    • 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
    tumoral     --over  
    associated with poor prognosis of patients with lung cancer
    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
    tumor  
    CFLAR downregulation is an early event required for endoplasmic reticulum stress-induced apoptosis in tumor cells
    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