Signal Transduction by DR3, a Death Domain-Containing Receptor Related to TNFR-1 and CD95

Chinnaiyan, Arul M.; O’Rourke, Karen; Yu, Guo Liang; Lyons, Robert H.; Garg, Manish; Duan, Delin; Xing, Lily; Gentz, Reiner; Ni, Jian; Dixit, Vishva M.

doi:10.1126/science.274.5289.990

Cited by 568 publications

(345 citation statements)

References 28 publications

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“…The plotted values represent the means+s.e.m. of three independent experiments cells of lymphoid lineage (Chinnaiyan et al, 1996b) while DR4 and DR5 are ubiquitously expressed by almost all cell types (Pan et al, 1997;Sheridan et al, 1997;MacFarlane et al, 1997). The H1299 and MCF-7 cells used in this study do express DR4 and DR5 mRNA (Sheikh et al, 1998).…”

Section: Discussionmentioning

confidence: 60%

Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1

et al. 1998

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Ultraviolet (UV)-irradiation has been shown to induce jun N-terminal kinase activity via aggregation-mediated activation of tumor necrosis factor receptor 1 (TNFR1) but the role of TNFR1 in mediating UV-induced apoptosis has not been explored. Using p53-null cells, we demonstrate that UV-stimulated ligand independent activation of TNFR1 plays a major role in mediating the apoptotic e ects of UV-irradiation. UV-irradiation and TNFa acted in a synergistic manner to induce apoptosis. UV-irradiation stimulated the aggregation-mediated activation of TNFR1 which was coupled with activation of caspase 8, the most proximal caspase in TNFa signaling pathway. CrmA and the dominant negative versions of FADD, caspase 8 and caspase 10, that block the apoptotic axis of TNFR1 at di erent levels, also independently inhibited the UV-induced apoptosis. The engagement of the membrane initiated events was speci®c for UV-irradiation since neither CrmA nor the dominant negative FADD, caspase 8 or caspase 10 blocked the ionizing radiation-induced apoptosis. Cisplatin and melphalan, the UV-mimetic agents known to elicit UVtype DNA damage, also induced apoptosis but di ered from UV in that both of the former agents engaged the caspase cascade at a level distal to FADD. Consistent with these ®ndings cisplatin also did not stimulate TNFR1 aggregation. Together these results indicate that DNA damage per se was not su cient to activate the membrane TNFR1. Based on our results we propose that the plasma membrane initiated events play a predominant role in mediating UV-irradiation-induced apoptosis and that UV-irradiation appears to engage the apoptotic axis of TNFR1 and perhaps those of other membrane death receptors to transduce its apoptotic signals.

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Section: Discussionmentioning

confidence: 60%

Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1

et al. 1998

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“…The action of CrmA on caspase-8 may also account for CrmA inhibition of apoptosis induced by tumor necrosis factor (TNF) (Enari et al, 1995;Los et al, 1995; and by a novel death domain-containing receptor, DR3/WSL-1, related to Fas and TNF receptor 1 (TNFR1) . TNF binding to TNFR1 and the activation of DR3 can recruit pro-caspase-8 by forming TNFR1-TRADD-FADD-pro-caspase-8 and DR3-TRADD-FADD-pro-caspase-8 complexes (Boldin et al, 1996;Chinnaiyan et al, 1996a;Fraser and Evan, 1996;Hsu et al, 1996). Froelich et al have recently implied that adenovirus-mediated delivery of granzyme B into Jurkat cells induces apoptosis by activating a protease upstream of caspases-3, -6/a, and -7/a.…”

Section: Discussionmentioning

confidence: 99%

Affinity labeling displays the stepwise activation of ICE-related proteases by Fas, staurosporine, and CrmA-sensitive caspase-8

et al. 1997

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The activation of multiple interleukin-1b converting enzyme-related proteases (caspases) in apoptotic mammalian cells raises questions as to whether the multiple active caspases have distinct roles in apoptotic execution as well as how these proteases are organized in apoptotic signaling pathways. Here we used an a nity-labeling agent, YV(bio)KD-aomk, to investigate the caspases activated during apoptotic cell death. YV(bio)KD-aomk identi®ed six distinct polypeptides corresponding to active caspases in Fas-stimulated Jurkat T cells. On staurosporine treatment, four polypeptides were detected. Competition experiments showed that the labeled caspases have distinct substrate preferences. Stepwise appearance of the labeled caspases in each cell death event was consistent with the view that the activated caspases are organized into protease cascades. Moreover, we found that stepwise activation of caspases similar to that induced by Fas ligation is triggered by exposing non-apoptotic Jurkat cell extracts to caspase-8 (MACH/FLICE/Mch5). Conversely, CrmA protein, a viral suppressor of Fas-induced apoptosis, inhibited the protease activity of caspase-8. Overall, these ®ndings provide evidence that caspase-8, a CrmA-sensitive protease, is responsible for initiating the stepwise activation of multiple caspases in Fas-stimulated cells.

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“…DR-3 is a member of the apoptosis-inducing tumor necrosis factor (TNF) receptor superfamily that includes Fas (12)(13)(14)(15)(16), and its promoter region near the translation start site contains GATA, Oct-1, and two Sp1 binding sites, but without containing either the TATA or the CAAT box. Sp1 is a ubiquitously expressed zinc-finger transcription factor that supports messenger RNA (mRNA) expression in a variety of eukaryotic genes that lack a functional TATA box (17,18), and this may be important for synovial cell activation.…”

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confidence: 99%

Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells

Takami

Osawa

Miura

et al. 2006

Arthritis & Rheumatism

138

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Objective. To examine the promoter activity and protein expression of the death receptor 3 gene DR3, a member of the apoptosis-inducing Fas gene family, with particular reference to the methylation status of its promoter region in rheumatoid arthritis (RA).Methods. Genomic DNA was prepared from peripheral blood mononuclear cells obtained from healthy individuals and from patients with RA and synovial cells obtained from patients with RA and osteoarthritis. The methylation status of the DR3 promoter was analyzed by bisulfite genomic sequencing and methylation-specific polymerase chain reaction techniques. Gene promoter activity and protein expression were examined using the luciferase reporter and Western blotting techniques.Results. The promoter region of the DR3 gene contained many CpG motifs, including one CpG island that was specifically hypermethylated in synovial cells from patients with RA. Promoter assays showed that the promoter CpG island was essential for the transactivation of the DR3 gene and that forced hypermethylation of the CpG island with the bacterial methylase Sss I in vitro resulted in inhibition of the DR3 gene expression.

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Signal Transduction by DR3, a Death Domain-Containing Receptor Related to TNFR-1 and CD95

Cited by 568 publications

References 28 publications

Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1

Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1

Affinity labeling displays the stepwise activation of ICE-related proteases by Fas, staurosporine, and CrmA-sensitive caspase-8

Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells

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