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FLASH GENE

Symbol

TNF

contributors: mct/pgu - updated : 24-06-2022

HGNC name	tumor necrosis factor (TNF superfamily, member 2)
HGNC id	11892

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

text	containing ARE elements in the 3'utr of mRNA

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000594 4 - 1669 NP_000585 - 233 - 2006 16908863

EXPRESSION

Type	ubiquitous

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 Cardiovascular heart       moderately Digestive intestine large intestine colon   lowly   pharynx       moderately Lymphoid/Immune lymph node       highly Reproductive female system placenta     lowly   male system prostate     highly Respiratory lung       highly Urinary bladder       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective       moderately

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Lymphoid/Immune macrophage

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
	TNF promotes RPE cell migration by inducing MMP9 expression through activation of AKT1/ MTOR, but not CRTC2 signaling
	LEP, RETN, TNF may have differentiating roles in the pathogenesis of Systemic sclerosis (SSc)

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
	IL1A stimulates cardiac myofibroblasts (CMF) to express IL1B, TNF, and IL6 via specific signaling pathways
	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
	promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression
	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
	can stimulate various chemotactic cytokines, including TNF and play a critical role in macrophage chemotaxis
	TNF promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP9) expression
	MTOR but not CRTC2 is required for TNF-induced RPE cell migration
	omentin inhibited TNF-activated signal pathway of NFKB1 by preventing NFKB1 inhibitory protein (NFKBIA) degradation and NFKB1/DNA binding activity
	correlation between ADM and TNF that could hypothesise the existence of a complex interaction between ADM and this inflammatory cytokine
	TNF caused a significant suppression of a dual specificity phosphatase, DUSP4, that regulates ERK1/2 activation
	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
	TNF-induced apoptosis leads to CASP8-dependent PAWR-cleavage followed by nuclear accumulation of the C-terminal PAWR (132-340) fragment, which then induces apoptosis
	TNF-mediated suppression of steroidogenesis involves HDAC7 in Leydig cells
	TNF activates HUWE1 by inducing the dissociation of HUWE1 from its inhibitor CDKN2A
	TNF confers cardioprotection through ectopic expression of keratins KRT8 and KRT18
	CHRM3-induced activation of MAPK14 might contribute to the maintenance of epithelial barrier function through down-regulation of TNF signalling and activation of EGFR
	TNF drives CCL4 expression in THP-1 monocytic cells/macrophages via the activation of SAPK/JNK and NFKB1 pathways
	TNF regulates the induction of MACC1 via RELA and the transcription factor JUN in Colorectal cancer cells
	crucial role of BCL3, in regulating TNF-induced hepatic cell death

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function 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 constitutional     --over   with TNF, TNFSF13B, TNFSF13 in Behcet disease

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
	System Type Disorder Pubmed blood     artificial modulation of TNF production could be a promising therapeutic approach to Fanconi anemia immunology autoimmune articular antibodies specific as therapeutic targets in rheumatoid arthritis

ANIMAL & CELL MODELS