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Tumor Necrosis Factor (TNF superfamily, member 2) (TNF) Homo sapiensThe TNF gene (map locus 6p21.3) product, tumor necrosis factor ligand precursor, TNF-alpha, is a 233 (25.6 kDa) amino acid-long type II transmembrane protein that organizes into stable homotrimers from which soluble homotrimeric cytokine, sTNF-alpha, can be released by the metalloprotease TNF alpha converting enzyme (TACE), ADAM17, CD156b. Each 17 kDa protomer in the soluble trimer is 157 amino acids long. TNF-alpha has a short (35aa) N-terminal cytoplasmic tail with a phosphorylation site at Ser2. Both the membrane-bound and the soluble forms of TNF-alpha can initiate cell signaling. TNF-alpha mediates its signal through two receptors, TNF-R1 (CD120a, p55/60) and TNF-R2 (CD120b; p75/80). The widely expressed constitutive receptor, TNF-R1, is activated by both forms of TNF-alpha; whereas, the immune restricted TNF-R2 responds only to the membrane-bound form. Both TNF receptors form trimers that are inactivated by the association of the inhibitory protein SODD, BAG4, which occupies their intracellular death domains (DD). Binding of TNF-alpha induces the conformation-dependent release of SODD and enables the binding of the multifunctional adaptor protein, TNF associated death domain, TRADD. TRADD binding enables the activation of three major signaling pathways that lead to mobilization of the transcription factors NFkappaB and JNK and/or apoptosis through caspase 8. NFkappaB regulates genes involved with cell-survival (anti-apoptosis), proliferation and the inflammatory response. JNK mediates cell differentiation, proliferation and is pro-apoptosis. Major targets of JNK include c-Jun (encodes AP-1) and ATF2 (encodes cyclic AMP-dependent transcription factor ATF-2, CRE-BP1). The major physiological effects of TNF-alpha signaling are proliferation (including tumorigenesis), differentiation, stimulation of an inflammatory response or apoptosis depending upon a complex signaling process that involves other factors and cell context. A variety of cells express TNF-alpha including neuronal cells (glial cells), fibroblasts, myocytes, mast cells, lymphoid cells and macrophages. Macrophages are a major producer of TNF-alpha. TNF-alpha is released in response to LPS, bacterial products and IL-1. Normal levels of TNF-alpha are associated with controlled inflammatory and a rapid form of host defense against infection; however, in excess it contributes to many disease conditions. Mutations in TNF-alpha have been linked to psoriatic arthritis, susceptibility to hepatitis B infection and cachexia. Dysregulation that leads to overproduction of TNF-alpha is being linked to a growing list of human diseases that include asthma, Alopecia Areata, Alzheimer’s disease (AD), ankyosing spondylitis, cerebral malaria, Crohn disease, cystic fibrosis, inflammatory bowel disease (IBD), insulin resistance, obesity, psoriasis, multiple sclerosis, rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), and various cancers. Chronic low level of TNF-alpha has emerged as a tumor promoter, Szlosarek P, et al. (2006) and master switch from inflammation to cancer phenotype, Sethi G, et al. (2008). Single nucleotide polymorphisms (SNP), especially within the promoter sequence of TNF-alpha, are becoming recognized markers for susceptibility to diseases such as Alzheimer’s disease and asthma. TNF-alpha produced by non-neural brain cells normally has a protective affect on neurons; however, in chronic stress pro-inflammatory conditions such as Alzheimer’s disease it can contribute to cell death. Alzheimer’s disease related dementia results from neural damage caused by neuro-inflammation induced in part by excess TNF-alpha expression. Factors that affect the level of TNF-alpha expression have been implicated in the age of onset and the frequency of AD. The TNF-alpha-308 G/A SNP has been shown to correlate with a younger age of AD onset, but not increased frequency, Lio D, (2006) and the presence of the A versus C form of TNF-alpha-863 C/A SNP has been associated with reduced odds of developing AD, Ramos EM, (2006). TNF-alpha release from mast cell granules has been implicated in asthmatic inflammation. SNP polymorphism, TNF-alpha -308G-A has recently been linked to risk of asthma, Shin et al. (2004); Kim HB, et al. (2008); Aoki T et al. (2006). Sigma offers antibodies, shRNAs and other products useful for the study of the Tumor Necrosis Factor. References: Aoki T, Hirota T, et al. (2006) An association between asthma and TNF-308G/A polymorphism: meta-analysis. J Hum Genet. 51: 677-685. |
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