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

• Herein, we have demonstrated that the induction of apoptosis by the proteasome inhibitors, MG-132 and PS-341 (bortezomib, Velcade), in primary CLL cells and the Burkitt lymphoma cell line, BJAB, is associated with up-regulation of TRAIL and its death receptors, DR4 and DR5 [13].
• Enhancement of TRAIL/Apo2L-mediated apoptosis by adriamycin through inducing DR4 and DR5 in renal cell carcinoma cells [14].
• Reconstitution of DR4 in the TRAIL-resistant A2780 ovarian cancer cell line was investigated with the demethylating agent 5-aza-2'-deoxycytidine and transient gene transfer [15].
• However, while net accumulation studies in the presence of 5 micrograms/ml verapamil reversed DOXR to parental values in LoVo colon adenocarcinoma cells, it only minimally decreased DOX resistance (12.6%) in HT1080/DR4 cells [16].
• Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression [17].

Biological context of TNFRSF10A

• The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, including TNFRSF10A and TNFRSF10B, are located within this chromosomal region [1].
• In this study we analyzed the complete coding region of TNFRSF10A and TNFRSF10B in a series of 32 MCL and 101 CLL samples and detected a single nucleotide polymorphism (SNP) in TNFRSF10A (A683C) with tumor specific allele distribution [1].
• We have isolated a new member of the tumor necrosis factor receptor (TNFR) family, designated DR5, which bears a high degree of sequence homology to DR4 [18].
• Nitrosylcobalamin promotes cell death via S nitrosylation of Apo2L/TRAIL receptor DR4 [2].
• Up-regulation of DR4 and DR5 was not preceded by the induction of their mRNA levels but was inhibited by cotreatment with cycloheximide [19].

Anatomical context of TNFRSF10A

• These variants do not induce apoptosis in DR4-responsive cell lines but show a large increase in biological activity in DR5-responsive cancer cell lines [20].
• TRAIL-R1, however, was never expressed at any time point examined, whereas the expression of TRAIL-R4, which showed a progressive increase in CD8(+) T cells, remained constant in NK cells [21].
• We addressed the expression of Fas, DR4, and DR5 in thyroid carcinoma cell lines and in 31 thyroid carcinoma specimens by Western blot analysis and immunohistochemistry, respectively, and tested the sensitivity of thyroid carcinoma cell lines to Fas- and TRAIL-induced apoptosis [22].
• Here, we examined whether the expression of TRAIL-R at the mRNA and protein level in a panel of 28 melanoma cell lines and melanocytes correlated with their sensitivity to TRAIL-induced apoptosis [3].
• This is a particular problem for lymphocytes that express DR4 and TRICK2 and are in constant circulation through TRAIL-expressing tissues [23].

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

• Here we show that TRAIL-R1 can associate with TRAIL-R2, suggesting that TRAIL may signal through heteroreceptor signaling complexes [12].
• (c) Surface expression of TRAIL-R1 and -R2 (but not TRAIL-R3 and -R4) showed an overall correlation with TRAIL-induced apoptosis [3].
• TRAIL-receptor and CD95 membrane expression was determined flow cytometrically [35].
• TRAIL-induced and DR4-mediated apoptosis in Jurkat cells is independent of DAP3 [36].
• Cisplatin showed synergistic effect on TRAIL-induced apoptosis in most HCC cell lines regardless of their p53 status and TRAIL-R1 was induced by cisplatin treatment in certain cell lines [37].

Analytical, diagnostic and therapeutic context of TNFRSF10A

• The endogenous RIP protein was detected by immunoprecipitation in the TRAIL-R1 complex after TRAIL treatment [38].
• Because these data suggested that sensitivity of ESFTs to TRAIL was mainly based on the presence of DR4/DR5, we investigated the presence of these receptors in 32 ESFT tissue sections by immunohistochemistry [4].
• Death receptor 4 (DR4) is one of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and triggers apoptosis on ligation with TRAIL or overexpression [30].
• RID induces the internalization of TRAIL-R1 from the cell surface, as shown by flow cytometry and indirect immunofluorescence for TRAIL-R1 [39].
• TRAIL-R1 is degraded, as indicated by the disappearance of the TRAIL-R1 immunofluorescence signal [39].

References