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FLASH GENE
Symbol TNF contributors: mct/pgu - updated : 24-04-2012
HGNC name tumor necrosis factor (TNF superfamily, member 2)
HGNC id 11892
Location 6p21.33      Physical location : 2.828.890 - 31.546.110
Synonym name
  • tumor necrosis factor alpha (cachectin)
  • TNF-Alpha
  • Synonym symbol(s) TNFA, TNFSF2, DIF, CACHECTIN, DADB-70P7.1, TNF-alpha
    DNA
    TYPE functioning gene
    STRUCTURE 2.76 kb     4 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   HRE
    motif repetitive sequence   other
    text structure
  • sequence CTCCCC in the promoter that binds to LITAF
  • monocyte-specific AT-rich DNase I-hypersensitive element located 7 kb upstream of the TNF gene (HSS-7), which serves as a matrix attachment region in monocytes, and potentially promoting TNF gene expression by acting as a Top2 substrate
  • MAPPING cloned Y linked N status confirmed
    Physical map
    HLA-B 6p21.3 major histocompatibility complex, class I, B MICA 6p21.3 MHC class I polypeptide-related sequence A HCP5 6p21.3 HLA complex P5 MICB 6p21.3 MHC class I polypeptide-related sequence B PPIP9 6p21.3 peptidylprolyl isomerase (cyclophilin) pseudogene 9 BAT1 6p21.33 HLA-B associated transcript 1 ATP6V1G2 6p21.3 ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G isoform 2 NFKBIL1 6p21.3 nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 1 LTA 6p21.3 lymphotoxin alpha (TNF superfamily, member 1) TNF 6p21.3 tumor necrosis factor (TNF superfamily, member 2) LTB 6p21.3 lymphotoxin beta (TNF superfamily, member 3) LST1 6p21.3 leukocyte specific transcript 1 NCR3 6p21.3 natural cytotoxicity triggering receptor 3 AIF1 6p21.3 allograft inflammatory factor 1 BAT2 6p21.33 HLA-B associated transcript 2 BAT3 6p21.33 HLA-B associated transcript 3 APOM 6p21.31 apolipoprotein M C6orf47 6p21.3 chromosome 6 open reading frame 47 BAT4 6p21.33 HLA-B associated transcript 4 CSNK2B 6p21.3 casein kinase 2, beta polypeptide LY6G5B 6p21.3 lymphocyte antigen 6 complex, locus G5B LY6G5C 6p21.3 lymphocyte antigen 6 complex, locus G5C BAT5 6p21.33 HLA-B associated transcript 5 LY6G6D 6p21.3 lymphocyte antigen 6 complex, locus G6D LY6G6E 6p21.3 lymphocyte antigen 6 complex, locus G6E LY6G6C 6p21.3 lymphocyte antigen 6 complex, locus G6C C6orf25 6p21.3 chromosome 6 open reading frame 25 DDAH2 6p21.3 dimethylarginine dimethylaminohydrolase 2
    RNA
    TRANSCRIPTS type messenger
    text containing ARE elements in the 3'utr of mRNA
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 - 1669 - 233 - 2006 16908863
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately
    Digestiveintestinelarge intestinecolon lowly
     pharynx   moderately
    Lymphoid/Immunelymph node   highly
    Reproductivefemale systemplacenta  lowly
     male systemprostate  highly
    Respiratorylung   highly
    Urinarybladder   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connective   moderately
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymphocyte
    Lymphoid/Immunemacrophage
    cell lineage
    cell lines
    fluid/secretion blood
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an extracellular C terminus, cleaved by ADAM17 to release the soluble 17kDa TNF alpha molecule
  • conjugated GlycoP
    mono polymer homomer , trimer
    isoforms Precursor synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17
    HOMOLOGY
    interspecies homolog to rattus Tnf (79.74 pc)
    homolog to murine Tnf (80.17 pc)
    Homologene
    FAMILY
  • tumor necrosis factor family
  • CATEGORY immunity/defense , signaling cytokine
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,endosome
    text type 2 membrane protein
    basic FUNCTION
  • potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion
  • potent proinflammatory cytokine involved in the cachexia
  • enhancing insulin resistance in peripheral tissues of cancer patients
  • mediating neuronal death in injured brain (by inducing resistance to the protective effect of IGF1)
  • involved in inflammatory and immune responses
  • stimulating the sphingomyelinase (SMPD1)
  • TNFalpha-induced ROS, cause oxidation and inhibition of JNK-inactivating phosphatases
  • critical cytokine mediating the downstream antiresorptive effects of TSH on the skeleton
  • inducing human follicular dendritic cells (FDC)proliferation by upregulated C8orf4 (TC1)
  • having a direct effect on small bowel iron transporter expression and function, leading to an inhibition of iron transport
  • mediates tumor angiogenesis through dysregulated FRAP1 signaling caused by suppression of TSC1 by IKBKB (revealing a novel mechanism of inflammation-mediated tumor angiogenesis)
  • significantly increased IL15-driven NK cell differentiation by increasing the expression of transcription factors that play crucial roles in NK cell maturation and inducing the NF-kappaB activity
  • through the activation of RFK, enhances the incorporation of FAD in NADPH oxidase enzymes, a critical step for the assembly and activation of NADPH oxidase
  • may contribute to mammary gland involution post lactation by, among other activities, eliciting LIF expression through ERK1/2 and AP1 activation (
  • activates both canonical and alternative NFKB signaling pathways in a time-dependent manner in skeletal muscle cells
  • its signaling maintains the ability of cortical synapses to express synaptic scaling
  • modulates prolonged NFE2L2-induced gene expression, which in turn regulates TNF-induced inflammatory responses
  • key regulator of bone matrix properties and composition that also inhibits terminal osteoblast differentiation
  • inhibits NPNT expression through the NFKB signaling pathway and down-regulation of NPNT influences the inhibition of osteoblast differentiation by TNF
  • importance of TNF in the pathogenesis of systemic lupus erythematosus
  • potential role of accrued changes in DNA methylation in the development of age-related inflammatory diseases, such as rheumatoid arthritis and polymyalgia rheumatica, in which TNF is a pivotal mediator
  • displays pathogenic activities in many autoimmune disorders
  • CELLULAR PROCESS cell life, proliferation/growth
    cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS inflammation
    PATHWAY
    metabolism
    signaling
  • hot responses against pathogens, NF-kappa B signaling pathway
  • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • OCT1 and NFKB
  • binding to LITAF
  • TNF, IL6, and leptin, which have been implicated in insulin sensitivity regulation, regulate the expression of STEAP4
  • TNF enhances the WNT/CTNNB1 signaling pathway by inducing MSX2 expression, which in turn suppresses adipocytic differentiation
  • TNFSF12 and TNF, downregulate Klotho expression through an NFKB-dependent mechanism
  • interaction with CASP8 (critical function of caspase-8 in regulating intestinal homeostasis and in protecting intestinal epithelial cells (IECs) from TNF-induced necroptotic cell death)
  • intreracting with UBD (plays an important role in mediating the function of TNF during tumorigenesis by inducing cell cycle deregulation and chromosomal instability, and by inhibiting apoptosis
  • RHBDF2, a proteolytically inactive member of the rhomboid family, is required for TNF release
  • correlation between ADM and TNF that could hypothesise the existence of a complex interaction between ADM and this inflammatory cytokine
  • up-regulates endometrial epithelial cell migration and MFGE8 production, which are critical steps required for the endometrial changes during menstrual cycle as well as during embryonic attachment and invasion
  • cell & other
    REGULATION
    induced by CREBBP in stimulated T cells
    IL1 beta
    repressed by LRRFIP1
    IL10 (inhibits transcription elongation of the human TNF gene in primary macrophages)
    Other regulated by PRKR in epithelial cells
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in inflammatory bowel disease
    constitutional     --over  
    in DM1 could contribute to the muscle wasting and insulin resistance that are characteristic of myotonic dystrophy
    constitutional     --over  
    modulates some catabolic features of TNF in chondrocytes
    constitutional     --over  
    in glomerulus and tubule of class III and IV lupus nephritis
    Susceptibility
  • to narcolepsy, cardiac sarcoidosis and systemic juvenile rheumatoid arthritis,
  • vascular dementia and Alzheimer's disease
  • to cerebral malaria, to inflammatory bowel disease (IBD)
  • severe sepsis following burn injury
  • to myasthenia gravis
  • childhood asthma
  • to rheumatoid arthritis
  • to systemic lupus erythematosus
  • Variant & Polymorphism SNP
  • a common polymorphism in the promoter region (C->A) associated with reduced circulating levels of TNF308G>A (asthma)-promoter polymorphism-857c in IBD
  • SNP associated with severe sepsis following burn injury
  • Candidate gene
    Marker
    Therapy target antibodies specific as therapeutic targets in rheumatoid arthritis
    SystemTypeDisorderPubmed
    blood  
    artificial modulation of TNF production could be a promising therapeutic approach to Fanconi anemia
    immunologyautoimmunearticular
    antibodies specific as therapeutic targets in rheumatoid arthritis
    ANIMAL & CELL MODELS