TNF (tumor necrosis factor (TNF superfamily, member 2))

2004-06-01   Fei Chen 

Health Effects Laboratory Division, NIOSH, 1095 Willowdale Rd, Morgantown, WV 26505, USA

Identity

HGNC
LOCATION
6p21.33
LOCUSID
ALIAS
DIF,TNF-alpha,TNFA,TNFSF2,TNLG1F
FUSION GENES

DNA/RNA

Description

The human TNFa gene has 4 exons spanning 2,762bp on the region of chromosome 6p21.3. The expression of TNFa gene generates a TNFa mRNA with size of 1,669nt. The 3-UTR region of TNFa mRNA contains a cluster of "AUUUA" elements that can be seen among many mRNAs with a short half-life, (AUUAUUUAUUAUUUAUUUAUUUAUUUAUUUAUUUA). A multiple NF-kB binding elements have been identified in the promoter region of TNFa gene.

Proteins

Atlas Image
The phylogenetic tree of TNF superfamily members.

Description

The human TNFa protein contains 233 amino acids with a predicated molecular weight of 25.6 kDa. The TNFa is produced initially in a membrane-associated form, which is then subjected to enzymatic remove of the N-terminal 76 amino acids by TACE/ADAM17, a TNFa converting enzyme, to generate the soluble 17kDa TNFa molecule that forms homotrimer. TNFa is the first prototypic member identified in the TNF superfamily (TNFSF, Fig.1 and Table 1). The human TNF superfamily currently has 19 well-characterized members. Other members, such as TNFSF19, TNFSF21, and TNFSF22 have not been well-established. Although each member has its own receptor preference, a functional overlapping, such as induction of apoptosis and NF-kB activation, has been observed among the majority of these members. In addition, as indicated in the phylogenetic tree in Figure 1, all of these members exhibit an evolutional conservation in their amino acid sequences, many of which show characteristics of type II membrane proteins. These features of TNF superfamily suggest that the members in this family may derived from the same ancestral gene. Several members contain a C-terminal conserved domain, named the TNF-homology domain that shares 20-30% of sequence identity. Except TNFSF1 (lymphotoxin a) and TNFSF3 (lymphotoxin b) that can form either homotrimer or heterotrimer, the active form of other members in this family is homotrimer.

Expression

TNFa is expressed virtually in every type of cells in response to inflammatory signals.

Localisation

membrane (type II membrane protein), extracellular soluble form, blood stream, and biological fluids.

Function

The most abundant cellular sources of TNFa are macrophage and monocyte. In response to inflammatory stimulation, macrophage or monocyte secretes TNFa that can induce apoptotic or necrotic cell death of certain tumor cell lines. In addition, TNFa is also capable of inducing cell proliferation and differentiation in many types of cells under certain circumstances. TNFa can be a pyrogen that causes fever by its direct action or by stimulation of interleukin 1 secretion. Sustained generation of TNFa in a variety of human diseases, especially cancer and severe infection, can cause cachexia-like syndrome. The increased expression of TNFa in adipose tissue was considered to be responsible for the development of obesity or diabetes due to the induction of insulin resistance by TNFa. All of above functional characteristics of TNFa are executed through specific members of the TNF receptor (TNFR) superfamily, mainly TNFR1, the primary receptor for soluble TNFa, and TNFR2, the predominant receptor for membrane-associated TNFa. These receptors trigger several intracellular signaling pathways, most importantly, the IkB kinase (IKK) and mitogen-activated protein kinase (MAPK) cascades, which govern gene expression through NF-kBNF-kB and AP-1 transcription factors, respectively.

Implicated in

Disease
Arthritis, asthma, cancer, cardiovascular disorders, diabetes, HIV infection and AIDS, inflammatory bowel disease, lung fibrosis, obesity, septic shock, etc..
Cytogenetics
Mutations or polymorphisms in the promoter or coding region of TNFa gene have been associated with asthma, celiac, septic shock susceptibility, silicosis, Psoriasis, GVHD, Leprosy, etc..

Bibliography

Pubmed IDLast YearTitleAuthors
129494982003Signalling pathways of the TNF superfamily: a double-edged sword.Aggarwal BB et al
145611802002The role of TNF and its family members in inflammation and cancer: lessons from gene deletion.Aggarwal BB et al
128605302003A co-evolution perspective of the TNFSF and TNFRSF families in the immune system.Collette Y et al
146982762004Inflammation: the link between insulin resistance, obesity and diabetes.Dandona P et al
127875592003The signaling adaptors and pathways activated by TNF superfamily.Dempsey PW et al
145803282003Adding facets to TNF signaling. The JNK angle.Liu ZG et al
129515802003Anti-TNF-alpha therapies: the next generation.Palladino MA et al
121024682002Tuberculous spondylitis: epidemiologic and clinical study in non-HIV patients from northwest Spain.Rodriguez-Gomez M et al
129652782003Tumour necrosis factor alpha: a potential target for the therapy of solid tumours.Szlosarek PW et al
149802172004Tumor necrosis factor: an apoptosis JuNKie?Varfolomeev EE et al
127875572003The TNF superfamily.Ware CF et al

Other Information

Locus ID:

NCBI: 7124
MIM: 191160
HGNC: 11892
Ensembl: ENSG00000232810

Variants:

dbSNP: 7124
ClinVar: 7124
TCGA: ENSG00000232810
COSMIC: TNF

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000232810ENST00000449264P01375
ENSG00000232810ENST00000449264Q5STB3

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Cytokine-cytokine receptor interactionKEGGko04060
mTOR signaling pathwayKEGGko04150
ApoptosisKEGGko04210
TGF-beta signaling pathwayKEGGko04350
Antigen processing and presentationKEGGko04612
Toll-like receptor signaling pathwayKEGGko04620
Hematopoietic cell lineageKEGGko04640
Natural killer cell mediated cytotoxicityKEGGko04650
T cell receptor signaling pathwayKEGGko04660
Fc epsilon RI signaling pathwayKEGGko04664
Adipocytokine signaling pathwayKEGGko04920
Type II diabetes mellitusKEGGko04930
Type I diabetes mellitusKEGGko04940
Alzheimer's diseaseKEGGko05010
Amyotrophic lateral sclerosis (ALS)KEGGko05014
AsthmaKEGGko05310
Systemic lupus erythematosusKEGGko05322
Allograft rejectionKEGGko05330
Graft-versus-host diseaseKEGGko05332
MAPK signaling pathwayKEGGhsa04010
Cytokine-cytokine receptor interactionKEGGhsa04060
mTOR signaling pathwayKEGGhsa04150
ApoptosisKEGGhsa04210
TGF-beta signaling pathwayKEGGhsa04350
Antigen processing and presentationKEGGhsa04612
Toll-like receptor signaling pathwayKEGGhsa04620
Hematopoietic cell lineageKEGGhsa04640
Natural killer cell mediated cytotoxicityKEGGhsa04650
T cell receptor signaling pathwayKEGGhsa04660
Fc epsilon RI signaling pathwayKEGGhsa04664
Adipocytokine signaling pathwayKEGGhsa04920
Type II diabetes mellitusKEGGhsa04930
Type I diabetes mellitusKEGGhsa04940
Alzheimer's diseaseKEGGhsa05010
Amyotrophic lateral sclerosis (ALS)KEGGhsa05014
AsthmaKEGGhsa05310
Systemic lupus erythematosusKEGGhsa05322
Allograft rejectionKEGGhsa05330
Graft-versus-host diseaseKEGGhsa05332
Hypertrophic cardiomyopathy (HCM)KEGGko05410
Hypertrophic cardiomyopathy (HCM)KEGGhsa05410
RIG-I-like receptor signaling pathwayKEGGko04622
RIG-I-like receptor signaling pathwayKEGGhsa04622
Dilated cardiomyopathyKEGGko05414
Dilated cardiomyopathyKEGGhsa05414
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
LeishmaniasisKEGGko05140
LeishmaniasisKEGGhsa05140
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
MalariaKEGGko05144
MalariaKEGGhsa05144
AmoebiasisKEGGko05146
AmoebiasisKEGGhsa05146
ToxoplasmosisKEGGko05145
ToxoplasmosisKEGGhsa05145
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
African trypanosomiasisKEGGko05143
African trypanosomiasisKEGGhsa05143
Rheumatoid arthritisKEGGko05323
Rheumatoid arthritisKEGGhsa05323
TuberculosisKEGGko05152
TuberculosisKEGGhsa05152
Influenza AKEGGko05164
Influenza AKEGGhsa05164
PertussisKEGGko05133
PertussisKEGGhsa05133
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
LegionellosisKEGGko05134
LegionellosisKEGGhsa05134
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
Hepatitis BKEGGhsa05161
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Inflammatory bowel disease (IBD)KEGGhsa05321
Inflammatory bowel disease (IBD)KEGGko05321
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
TNFR2 non-canonical NF-kB pathwayREACTOMER-HSA-5668541
Signal TransductionREACTOMER-HSA-162582
Death Receptor SignallingREACTOMER-HSA-73887
TNF signalingREACTOMER-HSA-75893
TNFR1-induced proapoptotic signalingREACTOMER-HSA-5357786
Developmental BiologyREACTOMER-HSA-1266738
Transcriptional regulation of white adipocyte differentiationREACTOMER-HSA-381340
Insulin resistanceKEGGhsa04931
TNFR1-induced NFkappaB signaling pathwayREACTOMER-HSA-5357956
TNFR1-mediated ceramide productionREACTOMER-HSA-5626978
Regulation of TNFR1 signalingREACTOMER-HSA-5357905
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Antifolate resistanceKEGGko01523
Antifolate resistanceKEGGhsa01523
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
Interleukin-10 signalingREACTOMER-HSA-6783783
IL-17 signaling pathwayKEGGko04657
Fluid shear stress and atherosclerosisKEGGko05418
IL-17 signaling pathwayKEGGhsa04657
Fluid shear stress and atherosclerosisKEGGhsa05418

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA10004adalimumabChemicalClinicalAnnotationassociatedPD12190096, 12847678, 16720636, 16909270, 17343250, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 26244882
PA164713366Tumor necrosis factor alpha (TNF-alpha) inhibitorsChemicalClinicalAnnotationassociatedPD12190096, 12847678, 15695296, 16720636, 16909270, 17343250, 17673491, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 25311255, 26244882
PA164784021ethambutolChemicalClinicalAnnotationassociatedPD22151084
PA164925725Toxic liver diseaseDiseaseClinicalAnnotationassociatedPD22151084
PA165108401Acute coronary syndromeDiseaseClinicalAnnotationassociatedPD18997459
PA165817016Kidney TransplantationDiseaseClinicalAnnotationassociatedPD18444945
PA166114377hand-foot syndromeDiseaseClinicalAnnotationassociatedPD22736425
PA443434Arthritis, RheumatoidDiseaseClinicalAnnotationassociatedPD12190096, 12847678, 15695296, 16720636, 16909270, 17343250, 17673491, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 25311255, 26244882
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD31616045
PA443815Crohn DiseaseDiseaseClinicalAnnotationassociatedPD12190096, 12847678, 15695296, 16720636, 16909270, 17343250, 17673491, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 25311255, 26244882
PA444447Carcinoma, HepatocellularDiseaseClinicalAnnotationassociatedPD22736425
PA444546HypersensitivityDiseaseClinicalAnnotationassociatedPD11294926
PA444620InflammationDiseaseClinicalAnnotationassociatedPD12190096, 12847678, 16720636, 16909270, 17343250, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 26244882
PA445451PsoriasisDiseaseClinicalAnnotationassociatedPD12190096, 12847678, 15695296, 16720636, 16909270, 17343250, 17673491, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 25311255, 26244882
PA445724Spondylitis, AnkylosingDiseaseClinicalAnnotationassociatedPD12190096, 12847678, 15695296, 16720636, 16909270, 17343250, 17673491, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 25311255, 26244882
PA445846ThrombocytopeniaDiseaseClinicalAnnotationassociatedPD31616045
PA445941TuberculosisDiseaseClinicalAnnotationassociatedPD22151084
PA446198Arthritis, PsoriaticDiseaseClinicalAnnotationassociatedPD12190096, 12847678, 16720636, 16909270, 17343250, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 26244882
PA447230HIVDiseaseClinicalAnnotationassociatedPD20887379
PA448500atorvastatinChemicalClinicalAnnotationassociatedPD18997459
PA448785carbamazepineChemicalClinicalAnnotationassociatedPD11294926
PA448803carboplatinChemicalClinicalAnnotationassociatedPD31616045
PA449167cyclosporineChemicalClinicalAnnotationassociatedPD18444945
PA449515etanerceptChemicalClinicalAnnotationassociatedPD12190096, 12847678, 16720636, 16909270, 17343250, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 26244882
PA449748gemcitabineChemicalClinicalAnnotationassociatedPD31616045
PA450112isoniazidChemicalClinicalAnnotationassociatedPD22151084
PA450566mycophenolate mofetilChemicalClinicalAnnotationassociatedPD18444945
PA451182pyrazinamideChemicalClinicalAnnotationassociatedPD22151084
PA451250rifampinChemicalClinicalAnnotationassociatedPD22151084
PA451494stavudineChemicalClinicalAnnotationassociatedPD20887379
PA452639infliximabChemicalClinicalAnnotationassociatedPD12190096, 12847678, 15695296, 16720636, 16909270, 17343250, 17673491, 18050183, 18438841, 18713756, 19365401, 22129793, 22760475, 22960943, 23057546, 24192118, 25311255, 26244882
PA7000sorafenibChemicalClinicalAnnotationassociatedPD22736425

References

Pubmed IDYearTitleCitations
195245122009Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha.729
171927852007Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.609
157665282005Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.589
184858762008TNF-alpha induces two distinct caspase-8 activation pathways.411
185839792008Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.395
229454162013A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers.361
243166712014Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis.342
147432162004A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.310
122970502002Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains.304
194110702009Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion.283

Citation

Fei Chen

TNF (tumor necrosis factor (TNF superfamily, member 2))

Atlas Genet Cytogenet Oncol Haematol. 2004-06-01

Online version: http://atlasgeneticsoncology.org/gene/319/tnf-(tumor-necrosis-factor-(tnf-superfamily-member-2))