Disease relevance of Tnfrsf10b

• Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases [1].
• Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity [1].
• In the present study, we have generated stable human colon cancer cell lines, in which the function of KILLER/DR5 was ablated using inducible RNA interference [2].
• Irradiation augmented TRAIL-induced apoptosis in breast cancer cells through up-regulation of DR5, and subsequent activation of caspases-3, -8 and -9 [3].
• More interestingly, in vivo studies performed in SCID/nonobese diabetic mice transplanted with autologous tumor and transferred with the specific CD4(+) CTL clone in combination with IFN-alpha resulted in an important APO2L/TRAIL-mediated tumor growth inhibition, which was prohibited by soluble TRAIL-R2 [4].

High impact information on Tnfrsf10b

• These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans [5].
• Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity [5].
• Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity [6].
• Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy [1].
• Natural Killer (NK) cells can recognize and kill MHC-incompatible normal bone marrow-derived cells [7].

Chemical compound and disease context of Tnfrsf10b

• We previously identified a 3' enhancer called the RAIDR5, which contained a DR5 retinoic acid response element (RARE) and was responsible for the retinoic acid (RA)-associated expression of the murine Hoxa-1 gene in teratocarcinoma cells [8].
• Antitumor efficacy was determined by treatment of nude mice bearing well-established s.c. DR5-positive 2LMP human breast cancer xenografts with TRA-8 alone or in combination with Adriamycin or paclitaxel [9].

Biological context of Tnfrsf10b

• MK induces apoptosis in mouse and human cells and inhibits colony growth of NIH3T3 cells [10].
• In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death [11].
• These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli [11].
• This synergistic effect is p53-dependent and may be the result of radiation-induced up-regulation of the TRAIL-receptor DR5 [12].
• However, it has not been demonstrated whether they regulate TRAIL-R2 via the promoter region [13].

Anatomical context of Tnfrsf10b

• We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development [11].
• When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain [11].
• DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse [11].
• At the blastocyst stage, both TRAIL and MK exhibit an apical staining pattern in the trophectoderm cells [14].
• We first isolated human hepatocytes from patients and showed that the human hepatocytes expressed Fas but no TRAIL death receptor DR4 and little DR5 on the cell surface [15].

Associations of Tnfrsf10b with chemical compounds

• MK contains an extracellular cysteine-rich domain, a transmembrane domain, and a cytoplasmic death-domain characteristic of Fas, tumor necrosis factor, and human TRAIL receptors [10].
• Finally, using the TUNEL assay, we demonstrated that MK induces apoptosis in blastocysts sensitized to TRAIL via actinomycin D [14].
• Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil [2].
• IFN-beta up-regulated the expression of TRAIL, while NS-398 increased the expression of TRAIL receptors (especially of death receptor 5) [16].
• Dox up-regulated the expression of the TRAIL receptor death receptor 5 (DR5) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to, but also against those resistant to, Dex- or Dox-induced apoptosis [17].

Regulatory relationships of Tnfrsf10b

• Using reverse transcription-polymerase chain reaction and confocal immunofluorescent microscopy, we found that both TRAIL and MK are expressed from the 1-cell through the blastocyst stage of murine preimplantation embryo development [14].
• PROBLEM: Natural Killer lymphocytes (NK cells) from the pregnant uterus and from other tissues in pregnant and nonpregnant mammals can be stimulated by interleukin-2 (IL-2) during culture to become Lymphokine Activated Killer (LAK) cells [18].

Other interactions of Tnfrsf10b

• DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro [11].
• DR5 knockout mice are compromised in radiation-induced apoptosis [11].
• Finally, the expression of additional apoptosis-inducing genes, including tumor necrosis factor receptor (TNFR), FADD, TRAIL, and DR5, was detected in mammalian testis [19].
• Among them, somatostatin is pivotal because affecting thyroid hormones turnover and consequently thymic and peripheral immune efficiency (Natural Killer, NK) cell activity [20].
• The expression of IL-15 (an important driver for innate immunity, Natural Killer cell activation, and IFN-gamma production) was abundant in air-exposed mice and was increased slightly in the lungs of mice with silicosis [21].

Analytical, diagnostic and therapeutic context of Tnfrsf10b

• Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor [10].
• Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model [9].
• Oligomerization of TRAIL-R2 was analyzed by size exclusion chromatography and confocal microscopy, and in vivo efficacy was examined in Colo205 xenograft model.RESULTS: KMTR2 specifically recognized TRAIL-R2 and induced apoptosis with or without cross-linking [22].
• Immunoprecipitations with the MOABs from 125I-labeled KR3598 cells (Dw5, DR5, MT2, MB3 homozygous, SB2, SB4) demonstrated that at least 4 different subpopulations of class II antigens were present in the lysate [23].
• Monoclonal antibodies were tested by ELISA for their abilities binding to sDR5 and by flow cytometry for the reactivities to surface DR5 of Jurkat cells [24].

References