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Gene Review

TNFRSF10A  -  tumor necrosis factor receptor superfamily...

Homo sapiens

Synonyms: APO2, Apo2, CD261, DR4, Death receptor 4, ...
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Disease relevance of TNFRSF10A

  • We found the rare allele of TNFRSF10A is more frequent in CLL, MCL, prostate cancer, bladder cancer and HNSCC [1].
  • Human melanoma (A375), renal carcinoma (ACHN), and ovarian carcinoma (NIH-OVCAR-3) cells were treated with NO-Cbl and subjected to the biotin switch assay; S-nitrosylated DR4 was detected in all three cell lines [2].
  • However, certain melanoma cell lines and clones were relatively resistant to TRAIL-induced apoptosis despite the absence of decoy receptors and moderate levels of TRAIL-R1 and -R2 expression [3].
  • Our finding of wide expression of DR4/DR5 in ESFT in vivo, in combination with their high sensitivity to TRAIL in vitro and the reported lack of toxicity of TRAIL in mice and monkeys, suggests that TRAIL may be a novel effective agent in the treatment of ESFTs [4].
  • We have found that different pancreatic cancer cell lines coexpress high-level TRAIL-R, Fas, and TNF-R1 but are strongly resistant to apoptosis triggered by the death receptors [5].
  • Significant downregulation of caspase-8, caspase-10 and of DR4 was characteristic for TRAIL-resistant, DR4-positive melanoma cells, and regained TRAIL sensitivity coincided with re-expression of these factors [6].

Psychiatry related information on TNFRSF10A

  • In contrast, the first-domain sequences of beta 1 molecules from these haplotypes are very different from each other and do not reflect the DR4, -7, -9 family relationship [7].
  • We used DRB1*0401-transgenic mice to understand the role of DR4 in susceptibility and sex bias in RA [8].

High impact information on TNFRSF10A

  • The frequencies of the insulin-dependent-diabetes-associated antigens HLA-DR3 and DR4 were not increased among the propositi, and diabetes did not cosegregate with HLA haplotypes in the informative families [9].
  • The receptor designated death receptor 5 (DR5) contained a cytoplasmic death domain and induced apoptosis much like DR4 [10].
  • TRAIL (also called Apo2L) belongs to the tumor necrosis factor family, activates rapid apoptosis in tumor cells, and binds to the death-signaling receptor DR4 [10].
  • The human receptor for TRAIL was found to be an undescribed member of the TNF-receptor family (designated death receptor-4, DR4) that contains a cytoplasmic "death domain" capable of engaging the cell suicide apparatus but not the nuclear factor kappa B pathway in the system studied [11].
  • TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB [12].

Chemical compound and disease context of TNFRSF10A


Biological context of TNFRSF10A


Anatomical context of TNFRSF10A


Associations of TNFRSF10A with chemical compounds

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug that selectively induces apoptosis in a variety of cancer cells by interacting with death receptors DR4 and DR5 [20].
  • The seven cysteine residues located in the cytoplasmic domain of DR4 were individually point mutated to alanines [2].
  • A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine [24].
  • TRAIL induces apoptosis in Adriamycin-resistant MCF7 cells already expressing high levels of death receptors DR4 and DR5 [25].
  • Two TRAIL-resistant lines that expressed DR4 contained an A-to-G alteration in the death domain encoding arginine instead of lysine at codon 441 [26].

Physical interactions of TNFRSF10A

  • Also, the study of DR4 subtypes minimized the potential contribution of polymorphic residues of the peptide-binding groove in the interaction with CD4 [27].
  • To begin to understand its regulation, we cloned a 1.8 Kb 5'-flanking region of the human DR4 gene and identified several putative binding sites for transcription factors including activator protein 1 (AP-1) [28].
  • Here we show that the signaling complex of DR4/DR5 is assembled in response to TRAIL binding [29].

Enzymatic interactions of TNFRSF10A

  • However, wild-type p53 or DNA-damaging agents completely lost their activity to increase transcriptional activity of a reporter construct with deleted DR4 p53BS [30].

Regulatory relationships of TNFRSF10A

  • Islets focally neoexpressed TRAIL-R1 and -R2 and intensely expressed TRAIL-R4 [31].
  • p21(WAF1/CIP1) inhibits initiator caspase cleavage by TRAIL death receptor DR4 [32].
  • Interferon-gamma (IFN-gamma) consistently upregulated levels of TRAIL-R1 [33].
  • Our previous study demonstrated that DR4 expression could be regulated in a p53-dependent fashion [30].
  • This effect was in accord with our observation that TG predominantly up-regulated both mRNA and protein expression of DR5, as well as DR4 mRNA while down-regulating DcR1 protein in GCT stromal-like tumor cells [34].

Other interactions of TNFRSF10A


Analytical, diagnostic and therapeutic context of TNFRSF10A


  1. Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer. Wolf, S., Mertens, D., Pscherer, A., Schroeter, P., Winkler, D., Gröne, H.J., Hofele, C., Hemminki, K., Kumar, R., Steineck, G., Döhner, H., Stilgenbauer, S., Lichter, P. Int. J. Cancer (2006) [Pubmed]
  2. Nitrosylcobalamin promotes cell death via S nitrosylation of Apo2L/TRAIL receptor DR4. Tang, Z., Bauer, J.A., Morrison, B., Lindner, D.J. Mol. Cell. Biol. (2006) [Pubmed]
  3. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Zhang, X.D., Franco, A., Myers, K., Gray, C., Nguyen, T., Hersey, P. Cancer Res. (1999) [Pubmed]
  4. Ewing's sarcoma family tumors are sensitive to tumor necrosis factor-related apoptosis-inducing ligand and express death receptor 4 and death receptor 5. Mitsiades, N., Poulaki, V., Mitsiades, C., Tsokos, M. Cancer Res. (2001) [Pubmed]
  5. Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro. Bai, J., Sui, J., Demirjian, A., Vollmer, C.M., Marasco, W., Callery, M.P. Cancer Res. (2005) [Pubmed]
  6. Resistance of melanoma cells to TRAIL does not result from upregulation of antiapoptotic proteins by NF-kappaB but is related to downregulation of initiator caspases and DR4. Kurbanov, B.M., Fecker, L.F., Geilen, C.C., Sterry, W., Eberle, J. Oncogene (2007) [Pubmed]
  7. Polymorphism of HLA-DR beta chains in DR4, -7, and -9 haplotypes: implications for the mechanisms of allelic variation. Gregersen, P.K., Moriuchi, T., Karr, R.W., Obata, F., Moriuchi, J., Maccari, J., Goldberg, D., Winchester, R.J., Silver, J. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  8. New humanized HLA-DR4-transgenic mice that mimic the sex bias of rheumatoid arthritis. Taneja, V., Behrens, M., Mangalam, A., Griffiths, M.M., Luthra, H.S., David, C.S. Arthritis Rheum. (2007) [Pubmed]
  9. Maturity-onset diabetes of youth in black Americans. Winter, W.E., Maclaren, N.K., Riley, W.J., Clarke, D.W., Kappy, M.S., Spillar, R.P. N. Engl. J. Med. (1987) [Pubmed]
  10. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Sheridan, J.P., Marsters, S.A., Pitti, R.M., Gurney, A., Skubatch, M., Baldwin, D., Ramakrishnan, L., Gray, C.L., Baker, K., Wood, W.I., Goddard, A.D., Godowski, P., Ashkenazi, A. Science (1997) [Pubmed]
  11. The receptor for the cytotoxic ligand TRAIL. Pan, G., O'Rourke, K., Chinnaiyan, A.M., Gentz, R., Ebner, R., Ni, J., Dixit, V.M. Science (1997) [Pubmed]
  12. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Schneider, P., Thome, M., Burns, K., Bodmer, J.L., Hofmann, K., Kataoka, T., Holler, N., Tschopp, J. Immunity (1997) [Pubmed]
  13. The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Kabore, A.F., Sun, J., Hu, X., McCrea, K., Johnston, J.B., Gibson, S.B. Apoptosis (2006) [Pubmed]
  14. Enhancement of TRAIL/Apo2L-mediated apoptosis by adriamycin through inducing DR4 and DR5 in renal cell carcinoma cells. Wu, X.X., Kakehi, Y., Mizutani, Y., Nishiyama, H., Kamoto, T., Megumi, Y., Ito, N., Ogawa, O. Int. J. Cancer (2003) [Pubmed]
  15. Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer. Horak, P., Pils, D., Haller, G., Pribill, I., Roessler, M., Tomek, S., Horvat, R., Zeillinger, R., Zielinski, C., Krainer, M. Mol. Cancer Res. (2005) [Pubmed]
  16. Pharmacological and biological evidence for differing mechanisms of doxorubicin resistance in two human tumor cell lines. Slovak, M.L., Hoeltge, G.A., Dalton, W.S., Trent, J.M. Cancer Res. (1988) [Pubmed]
  17. Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression. Ivanov, V.N., Hei, T.K. Exp. Cell Res. (2006) [Pubmed]
  18. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Chaudhary, P.M., Eby, M., Jasmin, A., Bookwalter, A., Murray, J., Hood, L. Immunity (1997) [Pubmed]
  19. Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. Nimmanapalli, R., Perkins, C.L., Orlando, M., O'Bryan, E., Nguyen, D., Bhalla, K.N. Cancer Res. (2001) [Pubmed]
  20. Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor. van der Sloot, A.M., Tur, V., Szegezdi, E., Mullally, M.M., Cool, R.H., Samali, A., Serrano, L., Quax, W.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  21. Activated human NK and CD8+ T cells express both TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors but are resistant to TRAIL-mediated cytotoxicity. Mirandola, P., Ponti, C., Gobbi, G., Sponzilli, I., Vaccarezza, M., Cocco, L., Zauli, G., Secchiero, P., Manzoli, F.A., Vitale, M. Blood (2004) [Pubmed]
  22. Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand. Mitsiades, N., Poulaki, V., Tseleni-Balafouta, S., Koutras, D.A., Stamenkovic, I. Cancer Res. (2000) [Pubmed]
  23. Lymphocyte inhibitor of TRAIL (TNF-related apoptosis-inducing ligand): a new receptor protecting lymphocytes from the death ligand TRAIL. Mongkolsapaya, J., Cowper, A.E., Xu, X.N., Morris, G., McMichael, A.J., Bell, J.I., Screaton, G.R. J. Immunol. (1998) [Pubmed]
  24. Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Gajate, C., Mollinedo, F. Blood (2007) [Pubmed]
  25. Synergistic interactions of chemotherapeutic drugs and tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand on apoptosis and on regression of breast carcinoma in vivo. Singh, T.R., Shankar, S., Chen, X., Asim, M., Srivastava, R.K. Cancer Res. (2003) [Pubmed]
  26. Molecular determinants of response to TRAIL in killing of normal and cancer cells. Kim, K., Fisher, M.J., Xu, S.Q., el-Deiry, W.S. Clin. Cancer Res. (2000) [Pubmed]
  27. HLA-DR polymorphism affects the interaction with CD4. Fleury, S., Thibodeau, J., Croteau, G., Labrecque, N., Aronson, H.E., Cantin, C., Long, E.O., Sékaly, R.P. J. Exp. Med. (1995) [Pubmed]
  28. Evidence that the human death receptor 4 is regulated by activator protein 1. Guan, B., Yue, P., Lotan, R., Sun, S.Y. Oncogene (2002) [Pubmed]
  29. Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Suliman, A., Lam, A., Datta, R., Srivastava, R.K. Oncogene (2001) [Pubmed]
  30. p53 upregulates death receptor 4 expression through an intronic p53 binding site. Liu, X., Yue, P., Khuri, F.R., Sun, S.Y. Cancer Res. (2004) [Pubmed]
  31. In chronic pancreatitis, widespread emergence of TRAIL receptors in epithelia coincides with neoexpression of TRAIL by pancreatic stellate cells of early fibrotic areas. Hasel, C., Dürr, S., Rau, B., Sträter, J., Schmid, R.M., Walczak, H., Bachem, M.G., Möller, P. Lab. Invest. (2003) [Pubmed]
  32. p21(WAF1/CIP1) inhibits initiator caspase cleavage by TRAIL death receptor DR4. Xu, S.Q., El-Deiry, W.S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  33. Expression of TNF-related apoptosis inducing ligand (TRAIL) on infiltrating cells and of TRAIL receptors on salivary glands in patients with Sjögren's syndrome. Matsumura, R., Umemiya, K., Kagami, M., Tomioka, H., Tanabe, E., Sugiyama, T., Sueishi, M., Kayagaki, N., Yagita, H., Okumura, K. Clinical and experimental rheumatology. (2002) [Pubmed]
  34. Thapsigargin potentiates TRAIL-induced apoptosis in giant cell tumor of bone. Huang, L., Xu, J., Li, K., Zheng, M.H., Kumta, S.M. Bone (2004) [Pubmed]
  35. Differential modulation of the TRAIL receptors and the CD95 receptor in colon carcinoma cell lines. van Geelen, C.M., de Vries, E.G., Le, T.K., van Weeghel, R.P., de Jong, S. Br. J. Cancer (2003) [Pubmed]
  36. TRAIL-induced apoptosis is independent of the mitochondrial apoptosis mediator DAP3. Berger, T., Kretzler, M. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  37. Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis, and the resistance is abolished by cisplatin. Shin, E.C., Seong, Y.R., Kim, C.H., Kim, H., Ahn, Y.S., Kim, K., Kim, S.J., Hong, S.S., Park, J.H. Exp. Mol. Med. (2002) [Pubmed]
  38. The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase. Lin, Y., Devin, A., Cook, A., Keane, M.M., Kelliher, M., Lipkowitz, S., Liu, Z.G. Mol. Cell. Biol. (2000) [Pubmed]
  39. Inhibition of TRAIL-induced apoptosis and forced internalization of TRAIL receptor 1 by adenovirus proteins. Tollefson, A.E., Toth, K., Doronin, K., Kuppuswamy, M., Doronina, O.A., Lichtenstein, D.L., Hermiston, T.W., Smith, C.A., Wold, W.S. J. Virol. (2001) [Pubmed]
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