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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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
	cellular Fas-associated death domain-like interleukin 1beta-converting enzyme inhibitory protein
	c-FLICE inhibitory proteins
	MACH-related inducer of toxicity
	FADD-like antiapoptotic molecule 1
	usurpin beta
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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003879 10 splicing 2215 NP_003870 55.3 480 - 1998 10200473 also called usurpin-alpha NM_001351590 10 splicing 11448 NP_001338519 52.6 462 - 1998 10200473 also called usurpin-beta NM_001351591 6 splicing 1152 NP_001338520 - 221 - 1998 10200473 also called usurpin-gamma NM_001127183 10 splicing 2004 NP_001120655 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) NM_001127184 6 splicing 1284 NP_001120656 - 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) variant 4 - splicing 1360 isoform 4 - 442 - 1998 10200473 also called I-FLICE NM_001202516 8 splicing 14507 NP_001189445 - 445 - 1998 10200473 NM_001202518 8 splicing 10960 NP_001189447 - 366 testis and skeletal muscle predominantly 1997 9228018 also called FLAME-1-alpha NM_001308043 5 splicing 4659 NP_001294972 - 250 - 1997 9228018 also called FLAME-1-beta NM_001351592 6 splicing 1522 NP_001338521 - 221 - 1997 9228018 also called FLAME-1-delta NM_001202517 9 splicing 14194 NP_001189446 - 384 - 1997 9380701 also called CLARP2 NM_001308042 10 splicing 11686 NP_001294971 - 462 - 1997 9228018 also called FlAME-1-epsilon NM_001351594 10 - 14341 NP_001338523 - 384 - - NM_001351593 9 - 14062 NP_001338522 - 384 - - NM_001202515 7 - 9734 NP_001189444 - 235 - - NM_001202519 9 - 11030 NP_001189448 - 366 - -

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic spleen         Cardiovascular heart       highly Digestive liver         Endocrine pancreas       highly Nervous brain         Respiratory lung         Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Epithelial secretory glandular endocrine   Epithelial secretory glandular exocrine   Lymphoid         Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic leukocyte

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
	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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed cancer digestive liver biology of CALM1-CFLAR binding may provide new therapeutic targets for cholangiocarcinoma and possibly other cancers cancer digestive colon targeting CFLAR and BIRC4 may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis cancer urinary   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