Alternative titles; symbols
HGNC Approved Gene Symbol: TNFRSF12A
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:3,020,368-3,022,383 (from NCBI)
Using a differential display approach to isolate cDNA fragments representing fibroblast growth factor-1 (FGF1; 131220)-inducible genes, Meighan-Mantha et al. (1999) isolated a mouse cDNA encoding, Tnfrsf12a, which they called Fn14. They characterized Fn14 as an immediate-early response gene. By searching an EST database with the mouse sequence, Feng et al. (2000) identified cDNAs encoding human TNFRSF12A. The predicted 129-amino acid FN14 protein, which shares 82% amino acid identity with the mouse sequence, contains a signal peptide, an extracellular domain, a membrane-anchoring domain, and a cytoplasmic domain. Northern blot analysis detected increased FN14 expression in response to FGF1, calf serum, or phorbol ester stimulation of human quiescent fibroblasts in vitro. A 1.2-kb FN14 transcript was expressed at high levels in heart, placenta, and kidney, at intermediate levels in lung, skeletal muscle, and pancreas, and at low levels in brain and liver. In addition, elevated FN14 expression was found in human liver cancer cell lines and hepatocellular carcinoma specimens. Expression of mouse Fn14 was upregulated in hepatocellular carcinoma nodules that develop in 2 different transgenic mouse models of hepatocarcinogenesis. Rapid induction of Fn14 expression occurred during mouse liver regeneration after partial hepatectomy. Feng et al. (2000) concluded that FN14 may play a role in hepatocyte growth control and liver neoplasia.
Using expression cloning and panning of an endothelial cell cDNA library with the C-terminal receptor-binding domain of TWEAK (TNFSF12; 602695) as the probe, followed by slide binding analysis, Wiley et al. (2001) isolated a cDNA encoding FN14, which they termed TWEAKR. Sequence analysis predicted that TWEAKR has a single extracellular cysteine-rich region that is homologous to those observed in TNFRSF1A (191190) and some other TNFR family members. TWEAKR also has a cytoplasmic TRAF (see TRAF2; 601895)-binding site. Different binding analyses indicated a physiologically relevant affinity between TWEAK and TWEAKR. GST-binding analysis showed an interaction of the TWEAKR cytoplasmic region with TRAF1 (601711), TRAF2, and, to a lesser extent, TRAF3 (601896), but not with other TRAFs tested. Northern blot analysis revealed expression of a 1.2-kb Tweakr transcript in rat aortic smooth muscle cells. Tweakr expression could be upregulated by a number of growth factors. Blocking of TWEAKR signaling inhibited the migration of renal microvascular cells in vitro, indicating that endogenous TWEAK regulates endothelial cell wound closure rates. Wiley et al. (2001) concluded that TWEAKR is a fully functional receptor for TWEAK and that the TWEAK-TWEAKR system plays a role in endothelial cell growth and migration.
Using FISH, Feng et al. (2000) mapped the TNFRSF12A gene to chromosome 16p13.3. Meighan-Mantha et al. (1999) mapped the mouse Tnfrsf12a gene to chromosome 17.
Using Western blot and immunocytochemistry, Jain et al. (2009) demonstrated high relative expression of Fn14 in cardiomyocytes, 3-fold greater than the overall tissue mean, with the level of expression second only to bronchial epithelial cells, smooth muscle cells, colorectal adenocarcinoma, and placenta. In mice, Fn14 expression was noted in ventricular cardiomyocytes at embryonic day 12.5, with little expression in atrial cells.
Feng, S.-L. Y., Guo, Y., Factor, V. M., Thorgeirsson, S. S., Bell, D. W., Testa, J. R., Peifley, K. A., Winkles, J. A. The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Am. J. Path. 156: 1253-1261, 2000. [PubMed: 10751351] [Full Text: https://doi.org/10.1016/S0002-9440(10)64996-6]
Jain, M., Jakubowski, A., Cui, L., Shi, J., Su, L., Bauer, M., Guan, J., Lim, C. C., Naito, Y., Thompson, J. S., Sam, F., Ambrose, C., and 9 others. A novel role for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the development of cardiac dysfunction and failure. Circulation 119: 2058-2068, 2009. [PubMed: 19349318] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.108.837286]
Meighan-Mantha, R. L., Hsu, D. K. W., Guo, Y., Brown, S. A. N., Feng, S.-L. Y., Peifley, K. A., Alberts, G. F., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Richards, C. M., Winkles, J. A. The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. J. Biol. Chem. 274: 33166-33176, 1999. [PubMed: 10551889] [Full Text: https://doi.org/10.1074/jbc.274.46.33166]
Wiley, S. R., Cassiano, L., Lofton, T., Davis-Smith, T., Winkles, J. A., Lindner, V., Liu, H., Daniel, T. O., Smith, C. A., Fanslow, W. C. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 15: 837-846, 2001. [PubMed: 11728344] [Full Text: https://doi.org/10.1016/s1074-7613(01)00232-1]