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| | The phylogenetic tree of TNF superfamily members. |
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| 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.
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| 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. |
| 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.. |
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