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Gene Review

TNFRSF25  -  tumor necrosis factor receptor superfamily...

Homo sapiens

Synonyms: APO-3, APO3, Apo-3, Apoptosis-inducing receptor AIR, Apoptosis-mediating receptor DR3, ...
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Disease relevance of TNFRSF25


Psychiatry related information on TNFRSF25


High impact information on TNFRSF25

  • We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13-p11 was in the DR3/X affected sibpair families (n=97; peak multipoint MLS at DXS1068=3.5, P=2.7x10(-4); single point MLS=4.5, P=2.7x10(-5)) [9].
  • An analysis of the major histocompatibility complex (MHC) HLA and complement types of 20 of the subjects with the lowest responses indicated a greater-than-expected number of homozygotes for the extended or fixed MHC haplotype [HLA-B8, SC01, DR3] [10].
  • WSL-1 also interacts specifically with the TNFR1-associated molecule TRADD [11].
  • The structure shows that the CLIP fragment binds to DR3 in a way almost identical to that in which antigenic peptides bind class II histocompatibility glycoproteins [12].
  • We have studied the molecular basis of HLA-DR polymorphism within such a group which includes the haplotypes DR3, DR5 and DRw6 [13].

Chemical compound and disease context of TNFRSF25


Biological context of TNFRSF25


Anatomical context of TNFRSF25


Associations of TNFRSF25 with chemical compounds

  • The additional N-linked glycan on mutant DR3 molecules isolated from the 10.24.6 cell line, which interferes with DM-enhanced CLIP release from DR3 in vitro, also affects the DM-DR interaction [24].
  • The C4A gene deletion was associated with HLA-A1, B8, DR3 in all but 1 patient who was HLA-DR3 negative [25].
  • Reticulin-antibody-positive relatives with or without jejunal mucosal atrophy were genetically similar to the probands of the families (DR3 gene frequencies 55.3%-60.0%) [26].
  • Like most DR3-type VD response elements, both IP9s are preferentially bound by VDR-RXR heterodimers with a 5'-RXR-VDR-3' polarity, whose transcriptional activity can be enhanced by costimulation with 9-cis retinoic acid [27].
  • VDR is functionally active in ATRA-treated Kasumi-1 cells because it efficiently heterodimerizes with retinoid X receptor, binds to a DR3-type vitamin D-responsive element, and activates the transcription of a vitamin D-responsive element-regulated reporter gene [28].

Physical interactions of TNFRSF25

  • Several other members of the TNF superfamily, including Fas and death receptors (DR)-3, -4, and -5, also contain intracellular death domains, but SODD only interacts with the death domain of DR3 [19].
  • Finally, cells isolated from WSL-1/TRAMP knockout mice are shown to retain their ability to interact with TWEAK [29].

Regulatory relationships of TNFRSF25

  • These data suggest that TL1A and DR3 is involved in atherosclerosis via the induction of pro-inflammatory cytokines/chemokines and decreasing plaque stability by inducing extracellular matrix degrading enzymes [1].
  • IL-12 plus IL-18 up-regulated DR3 expression in CCR9(+)CD4+ T cells but had negligible effect on CCR9(-)CD4+ T cells [30].
  • DR3 is capable of inducing both NF-kappa B activation and apoptosis when overexpressed in mammalian cells, although its ligand has not yet been identified [3].
  • Neuroblastoma cell lines with 1p deletion and MYCN-amplification expressed significantly lower levels of Apo-3 (P=0.009 and P=0.03, respectively) compared with neuroblastoma cell lines without 1p deletion or MYCN-amplification [31].

Other interactions of TNFRSF25

  • This protein, WSL-1, is most similar to TNFR1 itself, particularly in the death-domain region [11].
  • Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis [1].
  • However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or procaspase-8 seen in the signaling complex [21].
  • Interestingly, DR3-mediated apoptosis was induced in TF-1 cells in the presence of a NF-kappaB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-kappaB activation was responsible for resistance to apoptosis in these cells [21].
  • Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B [2].

Analytical, diagnostic and therapeutic context of TNFRSF25

  • Duplication of at least a portion of the DR3 gene, including the extracellular and transmembrane regions but not the cytoplasmic domain, was demonstrated by both fluorescence in situ hybridization and genomic Southern blotting [3].
  • Death receptors (Fas, TNFR-2, DR3, and TRAIL receptors) induce apoptosis upon ligation to cognate ligands or ectopic expression [32].
  • By indirect immunofluorescence and immunoperoxidase imaging and with gel filtration column chromatography, we observed rapid aggregation at the cell surface and the appearance of high molecular weight protein complexes primarily involving DR3, and DR3 and DR4 after camptothecin and VP-16 treatment, respectively [33].
  • HLA typing showed HLA-DR3 in 61% of patients (controls 22%, Pc less than 0.005) and the combination of DR3, DR4 in 43% (controls 3%, Pc less than 0.00001) [34].
  • To determine whether expression of DR was required for melanoma cells to be stimulatory, we first treated a stimulating cell line of DR3 allospecificity with anti-DR3-specific serum and demonstrated marked inhibition of its capacity to provoke blastogenesis [35].


  1. Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis. Kang, Y.J., Kim, W.J., Bae, H.U., Kim, D.I., Park, Y.B., Park, J.E., Kwon, B.S., Lee, W.H. Cytokine (2005) [Pubmed]
  2. Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B. Marsters, S.A., Sheridan, J.P., Donahue, C.J., Pitti, R.M., Gray, C.L., Goddard, A.D., Bauer, K.D., Ashkenazi, A. Curr. Biol. (1996) [Pubmed]
  3. Duplication of the DR3 gene on human chromosome 1p36 and its deletion in human neuroblastoma. Grenet, J., Valentine, V., Kitson, J., Li, H., Farrow, S.N., Kidd, V.J. Genomics (1998) [Pubmed]
  4. Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. Prehn, J.L., Mehdizadeh, S., Landers, C.J., Luo, X., Cha, S.C., Wei, P., Targan, S.R. Clin. Immunol. (2004) [Pubmed]
  5. A new death receptor 3 isoform: expression in human lymphoid cell lines and non-Hodgkin's lymphomas. Warzocha, K., Ribeiro, P., Charlot, C., Renard, N., Coiffier, B., Salles, G. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  6. Immunological associations in familial and non-familial Alzheimer patients and their families. Frecker, M.F., Pryse-Phillips, W.E., Strong, H.R. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. (1994) [Pubmed]
  7. Water-soluble lipopolymer as a gene carrier to corpus cavernosum. Lee, M., Ryu, J.K., Oh, S.M., Lee, E., Shin, H.Y., Song, S.U., Kim, S.W., Suh, J.K. Int. J. Impot. Res. (2005) [Pubmed]
  8. Increased frequency of DR3 antigen in alcoholic hepatitis and cirrhosis. Bron, B., Kubski, D., Widmann, J.J., von Fliedner, V., Jeannet, M. Hepatogastroenterology (1982) [Pubmed]
  9. A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Cucca, F., Goy, J.V., Kawaguchi, Y., Esposito, L., Merriman, M.E., Wilson, A.J., Cordell, H.J., Bain, S.C., Todd, J.A. Nat. Genet. (1998) [Pubmed]
  10. Genetic prediction of nonresponse to hepatitis B vaccine. Alper, C.A., Kruskall, M.S., Marcus-Bagley, D., Craven, D.E., Katz, A.J., Brink, S.J., Dienstag, J.L., Awdeh, Z., Yunis, E.J. N. Engl. J. Med. (1989) [Pubmed]
  11. A death-domain-containing receptor that mediates apoptosis. Kitson, J., Raven, T., Jiang, Y.P., Goeddel, D.V., Giles, K.M., Pun, K.T., Grinham, C.J., Brown, R., Farrow, S.N. Nature (1996) [Pubmed]
  12. The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3. Ghosh, P., Amaya, M., Mellins, E., Wiley, D.C. Nature (1995) [Pubmed]
  13. Polymorphism of human Ia antigens: gene conversion between two DR beta loci results in a new HLA-D/DR specificity. Gorski, J., Mach, B. Nature (1986) [Pubmed]
  14. Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. Schaffer, F.M., Palermos, J., Zhu, Z.B., Barger, B.O., Cooper, M.D., Volanakis, J.E. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  15. DRB genotyping supports recessive inheritance of DR3-associated susceptibility to insulin-dependent diabetes mellitus. Jenkins, D., Fletcher, J., Penny, M.A., Mijovic, C.H., Jacobs, K.H., Bradwell, A.R., Barnett, A.H. Am. J. Hum. Genet. (1991) [Pubmed]
  16. Intratumoral delivery of p2CMVmIL-12 using water-soluble lipopolymers. Mahato, R.I., Lee, M., Han , S., Maheshwari, A., Kim, S.W. Mol. Ther. (2001) [Pubmed]
  17. Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3. Price, P., Santoso, L., Mastaglia, F., Garlepp, M., Kok, C.C., Allcock, R., Laing, N. Tissue Antigens (2004) [Pubmed]
  18. Genetic markers in rheumatoid arthritis relationship to toxicity from D-penicillamine. Stockman, A., Zilko, P.J., Major, G.A., Tait, B.D., Property, D.N., Mathews, J.D., Hannah, M.C., McCluskey, J., Muirden, K.D. J. Rheumatol. (1986) [Pubmed]
  19. Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants. Al-Lamki, R.S., Wang, J., Thiru, S., Pritchard, N.R., Bradley, J.A., Pober, J.S., Bradley, J.R. Am. J. Pathol. (2003) [Pubmed]
  20. Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Chinnaiyan, A.M., O'Rourke, K., Yu, G.L., Lyons, R.H., Garg, M., Duan, D.R., Xing, L., Gentz, R., Ni, J., Dixit, V.M. Science (1996) [Pubmed]
  21. TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells. Wen, L., Zhuang, L., Luo, X., Wei, P. J. Biol. Chem. (2003) [Pubmed]
  22. Detection of methylated apoptosis-associated genes in urine sediments of bladder cancer patients. Friedrich, M.G., Weisenberger, D.J., Cheng, J.C., Chandrasoma, S., Siegmund, K.D., Gonzalgo, M.L., Toma, M.I., Huland, H., Yoo, C., Tsai, Y.C., Nichols, P.W., Bochner, B.H., Jones, P.A., Liang, G. Clin. Cancer Res. (2004) [Pubmed]
  23. TL1A synergizes with IL-12 and IL-18 to enhance IFN-gamma production in human T cells and NK cells. Papadakis, K.A., Prehn, J.L., Landers, C., Han, Q., Luo, X., Cha, S.C., Wei, P., Targan, S.R. J. Immunol. (2004) [Pubmed]
  24. Association between HLA-DM and HLA-DR in vivo. Sanderson, F., Thomas, C., Neefjes, J., Trowsdale, J. Immunity (1996) [Pubmed]
  25. Early-onset autoimmune hepatitis is associated with a C4A gene deletion. Scully, L.J., Toze, C., Sengar, D.P., Goldstein, R. Gastroenterology (1993) [Pubmed]
  26. Serological markers and HLA genes among healthy first-degree relatives of patients with coeliac disease. Mäki, M., Holm, K., Lipsanen, V., Hällström, O., Viander, M., Collin, P., Savilahti, E., Koskimies, S. Lancet (1991) [Pubmed]
  27. Natural vitamin D3 response elements formed by inverted palindromes: polarity-directed ligand sensitivity of vitamin D3 receptor-retinoid X receptor heterodimer-mediated transactivation. Schräder, M., Nayeri, S., Kahlen, J.P., Müller, K.M., Carlberg, C. Mol. Cell. Biol. (1995) [Pubmed]
  28. Induction of a functional vitamin D receptor in all-trans-retinoic acid-induced monocytic differentiation of M2-type leukemic blast cells. Manfredini, R., Trevisan, F., Grande, A., Tagliafico, E., Montanari, M., Lemoli, R., Visani, G., Tura, S., Ferrari, S., Ferrari, S. Cancer Res. (1999) [Pubmed]
  29. Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3). Kaptein, A., Jansen, M., Dilaver, G., Kitson, J., Dash, L., Wang, E., Owen, M.J., Bodmer, J.L., Tschopp, J., Farrow, S.N. FEBS Lett. (2000) [Pubmed]
  30. Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes. Papadakis, K.A., Zhu, D., Prehn, J.L., Landers, C., Avanesyan, A., Lafkas, G., Targan, S.R. J. Immunol. (2005) [Pubmed]
  31. Expression of Apo-3 and Apo-3L in primitive neuroectodermal tumours of the central and peripheral nervous system. Eggert, A., Grotzer, M.A., Zuzak, T.J., Ikegaki, N., Zhao, H., Brodeur, G.M. Eur. J. Cancer (2002) [Pubmed]
  32. Signalling by proteolysis: death receptors induce apoptosis. Muzio, M. Int. J. Clin. Lab. Res. (1998) [Pubmed]
  33. Camptothecin- and etoposide-induced apoptosis in human leukemia cells is independent of cell death receptor-3 and -4 aggregation but accelerates tumor necrosis factor-related apoptosis-inducing ligand-mediated cell death. Bergeron, S., Beauchemin, M., Bertrand, R. Mol. Cancer Ther. (2004) [Pubmed]
  34. High frequency of histocompatibility antigens HLA-DR3 and DR4 in herpes gestations. Shornick, J.K., Stastny, P., Gilliam, J.N. J. Clin. Invest. (1981) [Pubmed]
  35. HLA-DR histocompatibility leukocyte antigens permit cultured human melanoma cells from early but not advanced disease to stimulate autologous lymphocytes. Guerry, D., Alexander, M.A., Herlyn, M.F., Zehngebot, L.M., Mitchell, K.F., Zmijewski, C.M., Lusk, E.J. J. Clin. Invest. (1984) [Pubmed]
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