Death Receptor 5, a New Member of the TNFR Family, and DR4 Induce FADD-Dependent Apoptosis and Activate the NF-κB Pathway

Chaudhary, Preet M.; Eby, Michael T.; Jasmin, Alan; Bookwalter, Angela; Murray, Jessica; Hood, Leroy

doi:10.1016/s1074-7613(00)80400-8

Cited by 644 publications

(517 citation statements)

References 38 publications

(21 reference statements)

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“…In this context, however, it is important to remember that in addition to its role in the induction of apoptosis, TRAIL receptors are also known to activate the NF-B pathway. 28,29 The NF-B pathway that is believed to play an anti-apoptotic role and has been implicated in the pathogenesis of several human malignancies. 30 Several scenarios can be envisioned in which TRAIL predominantly activates the NF-B as compared to the apoptosis pathway in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Shivapurkar

Toyooka

et al. 2004

Intl Journal of Cancer

147

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TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 andDR5Several members of the tumor necrosis factor receptor superfamily, which includes tumor necrosis factor receptor 1, Fas (Apo-1/CD95), and the decoy receptors for TRAIL (Apo-2L), regulate programmed cell death (apoptosis). Upon engagement by their respective ligands, tumor necrosis factor receptor 1 and Fas recruit adaptor molecules and activate a cascade of cysteine proteases (caspases), the proteolytic activity of which results in apoptosis. The TRAIL-activated DR4 (also TNFRSF10A, Apo-2, TRAIL-R1) 1,2 and DR5 (also TNFRSF10B, KILLER/DR5, TRICK2, TRAIL-R3) receptors 2-4 have also been shown to initiate a caspase-mediated apoptotic pathway. 4 Death inducing DR4 and DR5 and the decoy receptors DcR1 (also TNFRSF10C, TRID, TRAIL-R3) and DcR2 (also TNFRSF10D, TRUNDD, TRAIL-R4) are structurally related, especially in their extracellular domains and are all located at 8p 21-22. 5,6 Decoy receptor DcR1 completely lacks the intra-cellular death domain and DcR2 contains a truncated, nonfunctional death domain and appear unable to induce apoptosis. The extracellular domains of DcR1 or DcR2 compete with those of DR4 or DR5 for TRAIL binding. Thus, based on the current knowledge, DcR1 or DcR2 are believed to inhibit apoptosis induction mediated through DR4 and DR5. 5 Inactivation of genes may occur via point mutations, allelic loss (LOH), homozygous deletions or by aberrant methylation. 7-9 Aberrant methylation of 5Ј gene promoter regions associated with gene silencing is an epigenetic phenomenon involving many genes observed in almost all cancer types, including breast cancers, lung cancers and mesotheliomas. 9 -18 We have demonstrated loss of expression (at RNA and protein level) of DR4 and DR5 in lung cancer cell lines, although the mechanism was not via methylation. 19 Recently, 20 it was reported that DcR1 and DcR2 expression are frequently silenced by aberrant methylation of 5Ј regions of these genes in pediatric tumor cell lines and neuroblastomas. In our study, we examined the methylation and expression status of DcR1, DcR2, DR4 and DR5 in breast and lung cancers and malignant mesothelioma (MM). We also examined the methylation status of TRAIL receptor genes in many other types of malignancies. We tried to correlate methylation status with clinical features of patients including survival and histological type in lung breast MM and prostate cancer. MATERIAL AND METHODS Cell linesCell lines were initiated by AFG (breast, lung, some MMs) or HIP (most MMs). [21][22][23] Twenty-seven lung cancer cell lines and 23 breast cancer cell lines and were grown in RPMI-1640 medium (Life Technologies Inc., Rockville, MD) supplemented with 5% FBS and incubated in 5% CO 2 at 37°C. Four non-malignant mesothelial primary cell cultures (HCC3466, HCC3468, HCC3469,

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Section: Discussionmentioning

confidence: 99%

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Shivapurkar

Toyooka

et al. 2004

Intl Journal of Cancer

147

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“…TRAIL is a cytokine of the TNF family which is expressed in most adult human tissues and is capable of killing transformed but not normal cells of di erent origins in a p53-independent manner (Pitti et al, 1996;Wiley et al, 1995;Kim et al, 2000) through binding to two proapoptotic receptors, DR4 and KILLER/DR5 (Chaudhary et al, 1997;MacFarlane et al, 1997;Screaton et al, 1997;Sheikh et al, 1997;Walczak et al, 1997;Wu et al, 1997). Normal cells also express TRAIL receptors but they appear to be protected from TRAIL-mediated killing through competition for ligand binding by two decoy receptors, TRID (Degli-Esposti et al, 1997a;MacFarlane et al, 1997;Pan et al, 1997;Schneider et al, 1997;Sheridan et al, 1997) and TRUNDD (Degli-Esposti et al, 1997b;Marsters et al, 1997;Meng et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site

2000

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KILLER/DR5, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor gene, has been shown to be induced by DNA damaging agents and radiation in a p53-dependent manner. Although TRAIL is a potential therapeutic agent for cancer, the induction mechanism of its receptors is poorly understood. Here we show the identi®cation of three p53 DNA-binding sites in the KILLER/DR5 genomic locus located upstream (BS1; 70.82 Kb) of the ATG site, within Intron 1 (BS2; +0.25 Kb downstream of the ATG) and within Intron 2 (BS3; +1.25 Kb downstream of the ATG). A modi®ed p53-binding and immunoselection protocol using a wildtype p53-expressing adenovirus vector (Ad-p53) was used to identify the binding sites and to show that each binding site can bind speci®cally to wild-type p53 protein (wt-p53). A reporter assay revealed that only BS2 could enhance luciferase expression driven by a basal promoter. We constructed a reporter plasmid carrying the genomic regulatory region of KILLER/DR5 including the three p53 DNA-binding sites but no additional basal promoter. The genomic fragment showed basal transcriptional activity which was induced by wt-p53 but not by mutant p53, and human papilloma virus E6 inhibited the p53-dependent activation. Mutation of BS2 abrogated not only the binding activity of wt-p53 but also the induction of the KILLER/DR5 genomic promoter-reporter gene, indicating that BS2 is responsible for the p53-dependent transactivation of KILLER/ DR5. In p53-wild-type but not -mutant or -null cell lines, doxorubicin treatment stabilized p53 protein, and increased speci®c binding to BS2 as revealed by EMSA, and upregulated the KILLER/DR5 promoter-luciferase reporter gene. These results suggest that the transactivation of KILLER/DR5 is directly regulated by exogenous or endogenous wt-p53 and establishes KILLER/DR5 as a p53 target gene that can signal apoptotic death.

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“…8,9 The mechanisms of hepatocyte toxicity by TRAIL remain unclear because of the difficulty in detection of TRAIL receptor expression in normal hepatocytes. TRAIL activates two distinct receptors, TRAIL-R1 (DR4) 10 and TRAIL-R2 (DR5), [11][12][13][14][15] both possess a death domain in their cytoplasmic tail that can engage the apoptotic machinery. Thus, it is presumed that TRAIL-R1 and TRAIL-R2 or both are involved in the hepatocyte toxicity.…”

Section: Introductionmentioning

confidence: 99%

Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2

et al. 2003

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in tumor cells without toxicity to normal cells, but some recombinant versions of TRAIL caused hepatocyte death. We generated fully human monoclonal antibodies (mAbs) that bind specifically to TRAIL receptor 1 (TRAIL-R1) and TRAIL receptor 2 (TRAIL-R2), which mediate apoptosis signal when they ligate with TRAIL, to investigate the contribution of each receptor to induce tumor cell apoptosis and hepatocyte toxicity. All of mAbs to TRAIL-R1 and TRAIL-R2 induced cell death in several cancer cell lines susceptible to TRAIL but not in human umbilical vein endothelial cells in vitro. Both anti-TRAIL-R1 mAbs and anti-TRAIL-R2 mAbs also caused cell death in hepatocytes. However, a subset of mAbs to TRAIL-R2, which was characterized by the TRAIL blocking activity, did not show strong hepatocyte toxicity. These results indicate that human normal hepatocytes are susceptible to both TRAIL-R1-and TRAIL-R2-mediated apoptosis signal.

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Death Receptor 5, a New Member of the TNFR Family, and DR4 Induce FADD-Dependent Apoptosis and Activate the NF-κB Pathway

Cited by 644 publications

References 38 publications

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site

Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2

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