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Gene Review

Tnfrsf12a  -  tumor necrosis factor receptor superfamily...

Mus musculus

Synonyms: AI255180, C87282, FGF-inducible 14, Fgfrp2, Fibroblast growth factor-inducible immediate-early response protein 14, ...
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Disease relevance of Tnfrsf12a


High impact information on Tnfrsf12a

  • Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb [1].
  • Following cardiotoxin injection, a known trigger for satellite cell-driven skeletal muscle regeneration, Fn14-deficient mice exhibited reduced inflammatory response and delayed muscle fiber regeneration compared with wild-type mice [4].
  • Coupled with our recent demonstration that TWEAK potentiates liver progenitor cell proliferation, the expression of Fn14 on all mesenchymal lineage progenitor cells supports a broad involvement of this pathway in other tissue injury and disease settings [4].
  • TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration [4].
  • By generating mice deficient in the TWEAK receptor Fn14, we further showed that Fn14-deficient primary myoblasts displayed significantly reduced proliferative capacity and altered myotube formation [4].

Chemical compound and disease context of Tnfrsf12a


Biological context of Tnfrsf12a

  • Here, we report that the human Fn14 homolog is located on chromosome 16p13.3 and encodes a 129-amino acid protein with approximately 82% sequence identity to the murine protein [2].
  • Some anti-human Fn14 mAbs we previously generated strongly cross-reacted with murine Fn14 and induced cell death in mFn14/L5178Y cells [6].
  • The Fn14 gene encodes a tumor necrosis-like weak inducer of apoptosis (TWEAK) receptor and is dramatically induced in DRG neurons after nerve damage, despite low expression in developing DRG neurons [7].
  • Following gonadotropin induction of ovulation, Fn14 is induced and could protect preovulatory follicles from excessive luteinization [8].
  • Blocking Fn14 signaling represents a novel approach with potential for the treatment of CNS autoimmunity [9].

Anatomical context of Tnfrsf12a

  • Recently, fibroblast growth factor-inducible 14 (Fn14) was suggested to be a receptor for TWEAK [10].
  • These results indicate that Fn14 may play a role in hepatocyte growth control and liver neoplasia [2].
  • We have used two experimental approaches, direct fluorescence microscopy and immunoprecipitation analysis of biotinylated cell surface proteins, to demonstrate that Fn14 is located on the plasma membrane [11].
  • To examine the biological consequences of constitutive Fn14 expression, we isolated NIH 3T3 cell lines expressing variable levels of epitope-tagged Fn14 and analyzed their phenotypic properties in vitro [11].
  • Fn14 expression in PC12 cells is also upregulated by nerve growth factor treatment [7].

Associations of Tnfrsf12a with chemical compounds

  • Likewise, ip injection of the Fn14 decoy enhanced serum progesterone levels with accompanying increases in transcript levels for several key steroidogenic enzymes [8].
  • The cytoskeletal localization of HPIP is mediated by an N-terminal leucine rich region (between aa 190-218) and can be disrupted by the microtubule destabilizing drug vincristine [12].
  • The HPIP C-terminal domain (aa 443-731) bears a nuclear export activity that is blocked by the CRM1 inhibitor Leptomycin B [12].

Other interactions of Tnfrsf12a


Analytical, diagnostic and therapeutic context of Tnfrsf12a

  • Ligation of the TWEAK receptor Fn14 by TWEAK has proinflammatory effects on fibroblasts, synoviocytes, and endothelial cells [14].
  • In situ hybridization analyses indicated that the Fn14 receptor is expressed in the granulosa and cumulus cells of preovulatory follicles and, to a lesser extent, in theca cells [8].
  • Based on DNA microarray analyses, we found that transcripts for the fibroblast growth factor-inducible-14 (Fn14) receptor are increased after LH/human chorionic gonadotropin (hCG) treatment of gonadotropin-primed immature mice or rats [8].
  • Vaccination with the extracellular domain of TWEAK or with Fn14 resulted in the induction of specific inhibitory antibodies and an amelioration of EAE signs in two different models in rats and mice [9].
  • Strikingly, electrophoretic mobility shift assays revealed that HPIP inhibits the ability of PBX-HOX heterodimers to bind to target sequences [15].


  1. TWEAK induces liver progenitor cell proliferation. Jakubowski, A., Ambrose, C., Parr, M., Lincecum, J.M., Wang, M.Z., Zheng, T.S., Browning, B., Michaelson, J.S., Baetscher, M., Baestcher, M., Wang, B., Bissell, D.M., Burkly, L.C. J. Clin. Invest. (2005) [Pubmed]
  2. The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Feng, S.L., Guo, Y., Factor, V.M., Thorgeirsson, S.S., Bell, D.W., Testa, J.R., Peifley, K.A., Winkles, J.A. Am. J. Pathol. (2000) [Pubmed]
  3. A soluble Fn14-Fc decoy receptor reduces infarct volume in a murine model of cerebral ischemia. Yepes, M., Brown, S.A., Moore, E.G., Smith, E.P., Lawrence, D.A., Winkles, J.A. Am. J. Pathol. (2005) [Pubmed]
  4. TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. Girgenrath, M., Weng, S., Kostek, C.A., Browning, B., Wang, M., Brown, S.A., Winkles, J.A., Michaelson, J.S., Allaire, N., Schneider, P., Scott, M.L., Hsu, Y.M., Yagita, H., Flavell, R.A., Miller, J.B., Burkly, L.C., Zheng, T.S. EMBO J. (2006) [Pubmed]
  5. Tumor necrosis factor-like weak inducer of apoptosis-induced neurodegeneration. Potrovita, I., Zhang, W., Burkly, L., Hahm, K., Lincecum, J., Wang, M.Z., Maurer, M.H., Rossner, M., Schneider, A., Schwaninger, M. J. Neurosci. (2004) [Pubmed]
  6. Characterization of murine TWEAK and its receptor (Fn14) by monoclonal antibodies. Nakayama, M., Harada, N., Okumura, K., Yagita, H. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  7. Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth. Tanabe, K., Bonilla, I., Winkles, J.A., Strittmatter, S.M. J. Neurosci. (2003) [Pubmed]
  8. Intraovarian tumor necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible-14 ligand-receptor system limits ovarian preovulatory follicles from excessive luteinization. De, A., Park, J.I., Kawamura, K., Chen, R., Klein, C., Rauch, R., Mulders, S.M., Sollewijn Gelpke, M.D., Hsueh, A.J. Mol. Endocrinol. (2006) [Pubmed]
  9. Targeting fibroblast growth factor-inducible-14 signaling protects from chronic relapsing experimental autoimmune encephalomyelitis. Mueller, A.M., Pedré, X., Kleiter, I., Hornberg, M., Steinbrecher, A., Giegerich, G. J. Neuroimmunol. (2005) [Pubmed]
  10. TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor. Polek, T.C., Talpaz, M., Darnay, B.G., Spivak-Kroizman, T. J. Biol. Chem. (2003) [Pubmed]
  11. The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. Meighan-Mantha, R.L., Hsu, D.K., Guo, Y., Brown, S.A., Feng, S.L., Peifley, K.A., Alberts, G.F., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Richards, C.M., Winkles, J.A. J. Biol. Chem. (1999) [Pubmed]
  12. Functional characterization of multiple domains involved in the subcellular localization of the hematopoietic Pbx interacting protein (HPIP). Abramovich, C., Chavez, E.A., Lansdorp, P.M., Humphries, R.K. Oncogene (2002) [Pubmed]
  13. The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation. Brown, S.A., Richards, C.M., Hanscom, H.N., Feng, S.L., Winkles, J.A. Biochem. J. (2003) [Pubmed]
  14. Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. Campbell, S., Burkly, L.C., Gao, H.X., Berman, J.W., Su, L., Browning, B., Zheng, T., Schiffer, L., Michaelson, J.S., Putterman, C. J. Immunol. (2006) [Pubmed]
  15. Functional cloning and characterization of a novel nonhomeodomain protein that inhibits the binding of PBX1-HOX complexes to DNA. Abramovich, C., Shen, W.F., Pineault, N., Imren, S., Montpetit, B., Largman, C., Humphries, R.K. J. Biol. Chem. (2000) [Pubmed]
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