Tumor necrosis factor

Details

Name
Tumor necrosis factor
Kind
protein
Synonyms
  • Cachectin
  • TNF-a
  • TNF-alpha
  • TNFA
  • TNFSF2
  • Tumor necrosis factor ligand superfamily member 2
Gene Name
TNF
UniProtKB Entry
P01375Swiss-Prot
Organism
Humans
NCBI Taxonomy ID
9606
Amino acid sequence
>lcl|BSEQ0001404|Tumor necrosis factor
MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGVIGPQR
EEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELR
DNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRE
TPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL
Number of residues
233
Molecular Weight
25644.15
Theoretical pI
6.92
GO Classification
Functions
death receptor agonist activity / transcription cis-regulatory region binding
Processes
antiviral innate immune response / astrocyte activation / calcium-mediated signaling / cellular response to amyloid-beta / cellular response to ionizing radiation / cellular response to lipopolysaccharide / cellular response to retinoic acid / cellular response to toxic substance / cellular response to type II interferon / circadian rhythm / cognition / detection of mechanical stimulus involved in sensory perception of pain / endothelial cell apoptotic process / inflammatory response to wounding / leukocyte migration involved in inflammatory response / liver regeneration / macrophage activation involved in immune response / microglial cell activation / negative regulation of amyloid-beta clearance / negative regulation of apoptotic signaling pathway / negative regulation of bile acid secretion / negative regulation of blood vessel endothelial cell migration / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of cytokine production involved in immune response / negative regulation of DNA-templated transcription / negative regulation of endothelial cell proliferation / negative regulation of heart rate / negative regulation of L-glutamate import across plasma membrane / negative regulation of miRNA transcription / negative regulation of mitotic cell cycle / negative regulation of myelination / negative regulation of neurogenesis / negative regulation of oxidative phosphorylation / negative regulation of protein-containing complex disassembly / negative regulation of signaling receptor activity / negative regulation of systemic arterial blood pressure / negative regulation of transcription by RNA polymerase II / negative regulation of vascular wound healing / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of action potential / positive regulation of amyloid-beta formation / positive regulation of blood microparticle formation / positive regulation of calcineurin-NFAT signaling cascade / positive regulation of canonical NF-kappaB signal transduction / positive regulation of cytokine production involved in inflammatory response / positive regulation of DNA biosynthetic process / positive regulation of DNA-binding transcription factor activity / positive regulation of DNA-templated transcription / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of fractalkine production / positive regulation of glial cell proliferation / positive regulation of hepatocyte proliferation / positive regulation of I-kappaB phosphorylation / positive regulation of inflammatory response / positive regulation of interleukin-1 beta production / positive regulation of interleukin-18 production / positive regulation of interleukin-33 production / positive regulation of JNK cascade / positive regulation of leukocyte adhesion to arterial endothelial cell / positive regulation of leukocyte adhesion to vascular endothelial cell / positive regulation of MAPK cascade / positive regulation of miRNA transcription / positive regulation of mitotic nuclear division / positive regulation of neuroinflammatory response / positive regulation of neuron apoptotic process / positive regulation of neutrophil activation / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of protein catabolic process / positive regulation of protein localization to plasma membrane / positive regulation of protein-containing complex assembly / positive regulation of protein-containing complex disassembly / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of synaptic transmission / positive regulation of synoviocyte proliferation / positive regulation of transcription by RNA polymerase II / positive regulation of type II interferon production / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / protein localization to plasma membrane / regulation of canonical NF-kappaB signal transduction / regulation of endothelial cell apoptotic process / regulation of fat cell differentiation / regulation of immunoglobulin production / regulation of membrane lipid metabolic process / regulation of metabolic process / regulation of reactive oxygen species metabolic process / regulation of synapse organization / regulation of synaptic transmission, glutamatergic / response to 3,3',5-triiodo-L-thyronine / response to activity / response to ethanol / response to fructose / response to gold nanoparticle / response to Gram-negative bacterium / response to hypoxia / response to isolation stress / response to L-glutamate / response to macrophage colony-stimulating factor / response to nutrient levels / response to xenobiotic stimulus / skeletal muscle contraction / toll-like receptor 3 signaling pathway / vascular endothelial growth factor production / vasodilation
Components
neuronal cell body
General Function
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Up-regulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:16829952, PubMed:22517918, PubMed:23396208). Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance (By similarity). Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6 (PubMed:12794819). Promotes osteoclastogenesis and therefore mediates bone resorption (By similarity)
Specific Function
Cytokine activity
Pfam Domain Function
Signal Regions
Not Available
Transmembrane Regions
36-56
Cellular Location
Cell membrane
Gene sequence
>lcl|BSEQ0021837|Tumor necrosis factor (TNF)
ATGAGCACTGAAAGCATGATCCGGGACGTGGAGCTGGCCGAGGAGGCGCTCCCCAAGAAG
ACAGGGGGGCCCCAGGGCTCCAGGCGGTGCTTGTTCCTCAGCCTCTTCTCCTTCCTGATC
GTGGCAGGCGCCACCACGCTCTTCTGCCTGCTGCACTTTGGAGTGATCGGCCCCCAGAGG
GAAGAGTTCCCCAGGGACCTCTCTCTAATCAGCCCTCTGGCCCAGGCAGTCAGATCATCT
TCTCGAACCCCGAGTGACAAGCCTGTAGCCCATGTTGTAGCAAACCCTCAAGCTGAGGGG
CAGCTCCAGTGGCTGAACCGCCGGGCCAATGCCCTCCTGGCCAATGGCGTGGAGCTGAGA
GATAACCAGCTGGTGGTGCCATCAGAGGGCCTGTACCTCATCTACTCCCAGGTCCTCTTC
AAGGGCCAAGGCTGCCCCTCCACCCATGTGCTCCTCACCCACACCATCAGCCGCATCGCC
GTCTCCTACCAGACCAAGGTCAACCTCCTCTCTGCCATCAAGAGCCCCTGCCAGAGGGAG
ACCCCAGAGGGGGCTGAGGCCAAGCCCTGGTATGAGCCCATCTATCTGGGAGGGGTCTTC
CAGCTGGAGAAGGGTGACCGACTCAGCGCTGAGATCAATCGGCCCGACTATCTCGACTTT
GCCGAGTCTGGGCAGGTCTACTTTGGGATCATTGCCCTGTGA
Chromosome Location
6
Locus
6p21.33
External Identifiers
ResourceLink
UniProtKB IDP01375
UniProtKB Entry NameTNFA_HUMAN
GenBank Protein ID339741
GenBank Gene IDM16441
GeneCard IDTNF
GenAtlas IDTNF
HGNC IDHGNC:11892
PDB ID(s)1A8M, 1TNF, 2AZ5, 2E7A, 2TUN, 2ZJC, 2ZPX, 3ALQ, 3IT8, 3L9J, 3WD5, 4G3Y, 4TSV, 4TWT, 4Y6O, 5M2I, 5M2J, 5M2M, 5MU8, 5TSW, 5UUI, 5WUX, 5YOY, 6OOY, 6OOZ, 6OP0, 6RMJ, 6X81, 6X82, 6X83, 6X85, 6X86, 7ASY, 7AT7, 7ATB, 7JRA, 7KP9, 7KPA, 7KPB, 7QLF, 7TA3, 7TA6
KEGG IDhsa:7124
NCBI Gene ID7124
General References
  1. Nedospasov SA, Shakhov AN, Turetskaya RL, Mett VA, Azizov MM, Georgiev GP, Korobko VG, Dobrynin VN, Filippov SA, Bystrov NS, et al.: Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) in the human genome. Cold Spring Harb Symp Quant Biol. 1986;51 Pt 1:611-24. [Article]
  2. Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV: Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20-1985 Jan 2;312(5996):724-9. [Article]
  3. Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB: Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. Nature. 1985 Feb 28-Mar 6;313(6005):803-6. [Article]
  4. Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW: Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985 Sep 11;13(17):6361-73. [Article]
  5. Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF: Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149-54. [Article]
  6. Marmenout A, Fransen L, Tavernier J, Van der Heyden J, Tizard R, Kawashima E, Shaw A, Johnson MJ, Semon D, Muller R, et al.: Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor. Eur J Biochem. 1985 Nov 4;152(3):515-22. [Article]
  7. Iris FJ, Bougueleret L, Prieur S, Caterina D, Primas G, Perrot V, Jurka J, Rodriguez-Tome P, Claverie JM, Dausset J, et al.: Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment. Nat Genet. 1993 Feb;3(2):137-45. [Article]
  8. Neville MJ, Campbell RD: A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC. J Immunol. 1999 Apr 15;162(8):4745-54. [Article]
  9. Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L: Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse. Genome Res. 2003 Dec;13(12):2621-36. [Article]
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  11. Takakura-Yamamoto R, Yamamoto S, Fukuda S, Kurimoto M: O-glycosylated species of natural human tumor-necrosis factor-alpha. Eur J Biochem. 1996 Jan 15;235(1-2):431-7. [Article]
  12. Pocsik E, Duda E, Wallach D: Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in transfected HeLa cells. J Inflamm. 1995;45(3):152-60. [Article]
  13. Watts AD, Hunt NH, Wanigasekara Y, Bloomfield G, Wallach D, Roufogalis BD, Chaudhri G: A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in 'reverse signalling'. EMBO J. 1999 Apr 15;18(8):2119-26. [Article]
  14. Van Ostade X, Tavernier J, Prange T, Fiers W: Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis. EMBO J. 1991 Apr;10(4):827-36. [Article]
  15. Stevenson FT, Bursten SL, Locksley RM, Lovett DH: Myristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues. J Exp Med. 1992 Oct 1;176(4):1053-62. [Article]
  16. Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD, et al.: Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature. 1997 Feb 20;385(6618):733-6. [Article]
  17. Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K, Kwiatkowski D: A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999 Jun;22(2):145-50. [Article]
  18. Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B: SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. [Article]
  19. Fluhrer R, Grammer G, Israel L, Condron MM, Haffner C, Friedmann E, Bohland C, Imhof A, Martoglio B, Teplow DB, Haass C: A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b. Nat Cell Biol. 2006 Aug;8(8):894-6. Epub 2006 Jul 9. [Article]
  20. Jinesh G G, Chunduru S, Kamat AM: Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-alpha but not through TRAIL and FasL. J Leukoc Biol. 2012 Jul;92(1):233-44. doi: 10.1189/jlb.1211623. Epub 2012 Apr 18. [Article]
  21. Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, Liu X, Xiao L, Chen X, Wan B, Chin YE, Zhang JZ: Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med. 2013 Mar;19(3):322-8. doi: 10.1038/nm.3085. Epub 2013 Feb 10. [Article]
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