Affinage

Showing TNFRSF10A — DR4 is a alias.

TNFRSF10A

Tumor necrosis factor receptor superfamily member 10A · UniProt O00220

Length
468 aa
Mass
50.1 kDa
Annotated
2026-06-10
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF10A (DR4/TRAIL-R1) is a cell-surface death receptor that initiates extrinsic apoptosis upon engagement by TRAIL/Apo2L, and is the primary mediator of TRAIL-induced cell death in tumor cells (PMID:28039489). Through its cytoplasmic death domain, DR4 recruits the adaptor FADD (along with TRADD and RIP), assembling a death-inducing signaling complex in which FADD is an obligatory mediator of apoptosis (PMID:9430227, PMID:9430228, PMID:9427646, PMID:10762627). Ligand engagement also nucleates a secondary complex retaining FADD and caspase-8 but additionally recruiting RIP1, TRAF2, and NEMO/IKKγ, thereby activating IKK/NF-κB, JNK, and p38 kinase pathways (PMID:16227629). DR4-driven caspase-8 activity cleaves BID to engage mitochondrial BAX, linking the receptor to the intrinsic apoptotic machinery during p53-driven genotoxic stress responses (PMID:22246181). DR4 signaling competence is set post-translationally: S-palmitoylation of its cytoplasmic domain drives lipid-raft localization and oligomerization (PMID:19090789), N-linked glycosylation promotes receptor aggregation and DISC formation (PMID:28186505), and S-nitrosylation at C336 enhances caspase-8 activation (PMID:16847314); surface availability is further governed by ARAP1-dependent trafficking to the plasma membrane (PMID:18165900) and by constitutive endocytosis and recycling that negatively regulate surface signaling (PMID:34660590). DR4 transcription is induced by DNA damage in a p53-dependent manner (PMID:11382926), by NF-κB/p65 via MEKK1 (PMID:18421578), and by a KAT2A·DDIT3·phospho-JUN complex acting at an AP-1 promoter element during ER stress (PMID:25770212), while it is repressed by the Hedgehog effector GLI3 and silenced by promoter hypermethylation to confer TRAIL resistance in cancer (PMID:20562908, PMID:15972852).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Established the core proximal signaling machinery of DR4 by identifying the death-domain adaptors that transduce its apoptotic and NF-κB signals.

    Evidence Co-IP of FADD/TRADD/RIP with DR4 and dominant-negative FADD blocking apoptosis; NF-κB reporter assays

    PMID:9430227 PMID:9430228

    Open questions at the time
    • Stoichiometry and order of adaptor assembly not resolved
    • Did not distinguish DISC from secondary complex
  2. 1997 Medium

    Raised the possibility that TRAIL signals through mixed receptor complexes by showing DR4 can associate with DR5.

    Evidence Co-IP of TRAIL-R1 with TRAIL-R2

    PMID:9430228

    Open questions at the time
    • Single Co-IP without reciprocal independent validation
    • Functional significance of heterocomplex unproven
  3. 1998 High

    Confirmed FADD as an obligatory component of DR4 apoptosis using a clean cellular loss-of-function approach.

    Evidence Stable dominant-negative GFP-FADD expression in HeLa cells with cell death assays

    PMID:9427646

    Open questions at the time
    • Dominant-negative may affect other death receptors
    • Did not address downstream caspase cascade specifics
  4. 2000 High

    Demonstrated that the DR4 death domain is genetically required for TRAIL-induced apoptosis via a natural deletion and rescue.

    Evidence Genomic deletion analysis in FaDu cells plus wild-type DR4 reconstitution and TRAIL cytotoxicity

    PMID:10762627

    Open questions at the time
    • Single cell-line context
    • Does not separate DR4 contribution from DR5 in other settings
  5. 2001 High

    Placed DR4 in the DNA-damage response by establishing it as a p53-inducible gene, connecting genotoxic stress to extrinsic apoptosis.

    Evidence RT-PCR/Western in irradiated and drug-treated cells with adenoviral p53 gain- and HPV E6 loss-of-function

    PMID:11382926

    Open questions at the time
    • Direct p53 binding site not mapped here
    • Whether induction is sufficient for apoptosis not addressed
  6. 2005 Medium

    Identified promoter hypermethylation as an epigenetic mechanism that silences DR4 and confers TRAIL resistance.

    Evidence Methylation-specific PCR, 5-aza-2'-deoxycytidine demethylation, and DR4 reconstitution in ovarian cancer cells

    PMID:15972852

    Open questions at the time
    • Single lab/cell line
    • Demethylation effects not gene-specific
  7. 2005 High

    Defined how DR4 activates kinase pathways by resolving a secondary signaling complex distinct from the DISC.

    Evidence Co-IP of secondary complex, siRNA of RIP1/TRAF2/NEMO, dominant-negatives, and kinase assays

    PMID:16227629

    Open questions at the time
    • Spatial/temporal relationship to primary DISC not fully resolved
    • Physiological outcome of NF-κB/JNK/p38 activation context-dependent
  8. 2006 High

    Revealed S-palmitoylation as a DR4-specific lipid modification required for raft localization and oligomerization, distinguishing it from DR5 and TNFR1.

    Evidence Palmitoylation assay, raft fractionation, oligomerization assays, comparison with DR5/TNFR1

    PMID:19090789

    Open questions at the time
    • Palmitoyltransferase responsible not identified
    • Dynamics/reversibility of palmitoylation unaddressed
  9. 2006 High

    Identified C336 S-nitrosylation as a functionally critical redox modification enhancing DR4 death signaling.

    Evidence Biotin-switch assay, systematic mutagenesis of all cytoplasmic cysteines, caspase-8 and viability assays

    PMID:16847314

    Open questions at the time
    • Endogenous NO source/enzyme not defined
    • Structural basis of how nitrosylation enhances signaling unknown
  10. 2008 High

    Showed direct NF-κB/p65 transcriptional control of DR4 downstream of MEKK1, adding a second stress-responsive induction route.

    Evidence Promoter reporter with site mutation, EMSA, ChIP, p65 RNAi, kinase-inactive MEKK1

    PMID:18421578

    Open questions at the time
    • Crosstalk with p53-driven induction not resolved
    • Conditions favoring NF-κB vs p53 control unclear
  11. 2008 High

    Identified ARAP1 as a trafficking adaptor controlling DR4 delivery to the cell surface, linking receptor abundance at the membrane to apoptotic competence.

    Evidence Yeast two-hybrid with DR4-ICP, Co-IP, confocal co-localization, siRNA with flow cytometry and death assays

    PMID:18165900

    Open questions at the time
    • GAP catalytic role in trafficking not dissected
    • Direct vs indirect interaction not fully established
  12. 2010 High

    Demonstrated Hedgehog-mediated repression of DR4 through GLI3 binding, explaining a transcriptional route to TRAIL resistance.

    Evidence Promoter reporter, ChIP, GLI1/2/3 and DR4 siRNA, death assays in cholangiocarcinoma

    PMID:20562908

    Open questions at the time
    • GLI3 repressor cofactors not identified
    • Generality beyond cholangiocarcinoma untested
  13. 2011 Medium

    Showed that raft-localized rather than total DR4 determines TRAIL sensitivity, refining the receptor-availability model.

    Evidence Sucrose-gradient raft fractionation, DR4 siRNA, nystatin disruption, apoptosis assays in NSCLC lines

    PMID:21769428

    Open questions at the time
    • Single-study two-cell-line comparison
    • Molecular trigger of raft redistribution not defined
  14. 2012 High

    Placed DR4 mechanistically within the p53 apoptosis decision, upstream of caspase-8/BID/BAX, linking extrinsic and intrinsic pathways.

    Evidence Isogenic epistasis, DR4 siRNA, caspase-8 inhibition, BID cleavage and cytochrome C release assays

    PMID:22246181

    Open questions at the time
    • Relative contribution of DR4 vs DR5 in p53 response not separated
    • Determinants of apoptosis vs arrest choice partly unresolved
  15. 2012 Medium

    Extended DR4 ligand biology beyond TRAIL by showing oligomeric Aβ binds DR4 to drive endothelial apoptosis.

    Evidence Receptor chimera binding, DR4/DR5 RNA silencing, caspase-8/9 and Bid cleavage assays

    PMID:22695614

    Open questions at the time
    • Single-study system (cerebral endothelial cells)
    • Physiological relevance and binding site not mapped
  16. 2015 High

    Defined an ER-stress transcriptional module (KAT2A·DDIT3·phospho-JUN) that activates DR4 via histone acetylation at an AP-1 promoter element.

    Evidence Co-IP, ChIP, AP-1 site reporter mutagenesis, KAT2A siRNA, H3K9/K14 acetylation Western

    PMID:25770212

    Open questions at the time
    • Integration with NF-κB and p53 inputs unresolved
    • Stimulus specificity of complex assembly unclear
  17. 2017 High

    Established DR4 as the primary TRAIL apoptosis mediator and a participant in ER-stress apoptosis, while distinguishing it from DR5 in being unable to drive migratory calcium signaling.

    Evidence TALEN-edited isogenic DR4/DR5 knockouts, Co-IP with FADD/caspase-8 under ER stress, calcium flux and motility assays

    PMID:28039489

    Open questions at the time
    • Mechanism for DR4's inability to flux calcium not defined
    • Cell-line dependence of receptor dominance
  18. 2017 High

    Showed N-linked glycosylation promotes DR4 aggregation and DISC formation and modulates viral immune evasion, defining a glycan-level control of signaling.

    Evidence Glycosylation-site mutagenesis, DISC IP, TRAIL- and UL141-binding assays, apoptosis readouts

    PMID:28186505

    Open questions at the time
    • Specific glycan structures involved not characterized
    • In vivo relevance of UL141 modulation untested
  19. 2021 High

    Demonstrated that constitutive endocytosis and recycling of DR4 negatively regulate surface TRAIL signaling, providing a dynamic control of receptor availability.

    Evidence Live-cell flow cytometry of internalization/recycling, receptor-selective TRAIL variant, brefeldin A/cycloheximide, sucrose endocytosis inhibition with cytotoxicity

    PMID:34660590

    Open questions at the time
    • Adaptors/machinery selecting clathrin-dependent vs independent routes unidentified
    • Signaling status of internalized receptor unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational modifications, trafficking routes, and competing transcriptional inputs are integrated to set DR4 surface density and signaling competence in a given cell remains unresolved.
  • No unified model linking palmitoylation, glycosylation, nitrosylation, ARAP1 trafficking, and endocytosis
  • Enzymes catalyzing palmitoylation and physiological NO-donor unknown
  • Hierarchy of p53, NF-κB, DDIT3/AP-1, and GLI3 transcriptional control not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ARAP1CASP8FADDNEMORIP1TNFRSF10BTRADDTRAF2
Complex memberships
DISC (death-inducing signaling complex)KAT2A·DDIT3·phospho-JUN promoter complexTRAIL secondary signaling complex (FADD/caspase-8/RIP1/TRAF2/NEMO)

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 DR4 (TRAIL-R1) recruits adaptor proteins FADD, TRADD, and RIP to its cytoplasmic death domain, and DR4-induced apoptosis is blocked by dominant-negative FADD, establishing FADD as a required mediator of DR4-initiated cell death. DR4 also activates NF-κB via a TRADD-dependent pathway. Co-immunoprecipitation of FADD/TRADD/RIP with DR4; dominant-negative FADD overexpression blocking apoptosis; NF-κB reporter assays Immunity High 9430227 9430228
1997 TRAIL-R1 (DR4) can physically associate with TRAIL-R2 (DR5), suggesting that TRAIL may signal through heteroreceptor complexes. Co-immunoprecipitation of TRAIL-R1 with TRAIL-R2 Immunity Medium 9430228
1998 Dominant-negative FADD (GFP-ΔF ADD) stably expressed in HeLa cells inhibits TRAIL-R/Apo2-induced cell death, confirming that FADD is an obligatory component of DR4 (TRAIL-R1) apoptotic signaling. Stable expression of GFP-tagged dominant-negative FADD in HeLa cells; cell death assays Current biology : CB High 9427646
2001 DR4 (TRAIL-R1) expression is induced by DNA-damaging agents (ionizing radiation, chemotherapeutics) predominantly in cells harboring wild-type p53; introduction of exogenous wild-type p53 up-regulates endogenous DR4, and inhibition of p53 (via HPV E6) suppresses DR4 induction, establishing DR4 as a DNA damage-inducible, p53-regulated gene. RT-PCR and Western blot in irradiated/drug-treated cells; adenoviral p53 introduction; HPV E6 transfection; transcription inhibitor (actinomycin D) blocking induction Journal of cellular physiology High 11382926
2005 Apo2L/TRAIL activates IKK, JNK, and p38 kinase pathways by assembling a secondary signaling complex downstream of the primary DISC. This secondary complex retains DISC components FADD and caspase-8 but additionally recruits RIP1, TRAF2, and NEMO/IKKγ. Secondary complex formation requires FADD and caspase-8 activity; JNK/p38 activation requires RIP1 and TRAF2; IKK activation requires NEMO. Co-immunoprecipitation of secondary complex components; siRNA knockdowns of RIP1, TRAF2, NEMO; dominant-negative constructs; kinase activity assays The Journal of biological chemistry High 16227629
2006 DR4 undergoes S-palmitoylation on its cytoplasmic domain, which is required for its localization to lipid rafts and its ability to oligomerize; DR5 and TNFR1 are not palmitoylated. Palmitoylation of DR4 is necessary for efficient TRAIL-induced death signal transmission. Palmitoylation assay (acyl-RAC or equivalent); lipid raft fractionation; oligomerization assays; comparison with DR5 and TNFR1 The Biochemical journal High 19090789
2006 DR4 is S-nitrosylated at cysteine C336 in its cytoplasmic domain following treatment with nitrosylcobalamin (NO-Cbl). C336A point mutation abolishes S-nitrosylation, reduces caspase-8 activation, and confers resistance to NO-Cbl- and TRAIL-induced apoptosis, identifying C336 as a functionally critical residue for death signaling. Biotin-switch assay for S-nitrosylation; site-directed mutagenesis of all seven cytoplasmic cysteines to alanine; caspase-8 activity assays; cell viability assays Molecular and cellular biology High 16847314
2008 NF-κB transcriptionally regulates DR4 expression in response to etoposide. The p65 subunit of NF-κB binds a functional NF-κB site in the DR4 promoter; mutation of this site abrogates luciferase induction; p65 knockdown by RNAi blocks etoposide-induced DR4 upregulation; MEKK1 kinase activity is required upstream of NF-κB for DR4 induction. Luciferase promoter reporter assays with NF-κB site mutation; EMSA; chromatin immunoprecipitation (ChIP); RNAi knockdown of p65; kinase-inactive MEKK1 expression Apoptosis : an international journal on programmed cell death High 18421578
2008 ARAP1 (an Arf/Rho GAP adapter protein) physically interacts with the intracellular portion (ICP) of DR4, co-localizes with DR4 in the ER/Golgi, plasma membrane, and early endosomes, and its knockdown reduces DR4 cell-surface levels and slows TRAIL-induced apoptosis, indicating ARAP1 regulates DR4 trafficking to the plasma membrane. Yeast two-hybrid screen with DR4-ICP; Co-immunoprecipitation of transfected ARAP1 with DR4; co-localization by confocal microscopy; siRNA knockdown with flow cytometry and cell death assays Apoptosis : an international journal on programmed cell death High 18165900
2015 DDIT3 (CHOP) interacts with phospho-JUN, and the DDIT3·phospho-JUN complex binds the AP-1 site (−304/−298) in the TNFRSF10A (DR4) promoter to drive expression. KAT2A physically interacts with the N-terminal region (aa 1–26) of DDIT3 and participates in a KAT2A·DDIT3·phospho-JUN complex that acetylates H3K9/K14, cooperatively upregulating DR4 during ER stress-mediated apoptosis. Co-immunoprecipitation; ChIP; luciferase promoter reporter assays with AP-1 site mutation; siRNA knockdown of KAT2A; Western blot for H3K9/K14 acetylation The Journal of biological chemistry High 25770212
2010 The transcription factor GLI3 binds the DR4 promoter and mediates Hedgehog pathway repression of DR4 expression. siRNA knockdown of GLI3 (but not GLI1 or GLI2) restores DR4 expression and TRAIL sensitivity in cholangiocarcinoma cells; DR4 knockdown mimics Hh-mediated TRAIL resistance. Luciferase promoter reporter assay; ChIP; siRNA knockdown of GLI1, GLI2, GLI3; DR4 siRNA knockdown; cell death assays Oncogene High 20562908
2012 p53-dependent activation of the DR4 death receptor pathway, followed by caspase-8-mediated cleavage of BID, and BID-dependent activation of mitochondria-poised BAX, is a key determinant driving cells toward apoptosis versus proliferation arrest after p53 activation by genotoxic stress. Genetic epistasis using isogenic cell lines; siRNA knockdown of DR4; caspase-8 inhibition; BID cleavage assays; cytochrome C release assays; caspase activation assays The EMBO journal High 22246181
2017 N-linked glycosylation of TRAIL-R1 (DR4) promotes TRAIL-induced apoptosis: N-glycosylation-defective DR4 mutants show reduced TRAIL receptor aggregation and reduced DISC formation without affecting TRAIL-binding affinity. Additionally, N-glycosylation of DR4 reduces its binding affinity for the CMV immune evasion protein UL141. Site-directed mutagenesis of N-glycosylation sites; DISC immunoprecipitation; TRAIL-binding affinity assays; UL141 binding assays; apoptosis assays with N-glyc-deficient mutants Cell death and differentiation High 28186505
2017 Using TALEN-based gene editing, TRAIL-R1 (DR4) was shown to be the primary mediator of TRAIL-induced apoptosis in tested tumor cell lines. DR4 also mediates apoptosis during ER stress (co-immunoprecipitating with FADD and caspase-8 upon ER stress induction); however, unlike TRAIL-R2, DR4 is unable to trigger cell migration because it cannot induce calcium flux. TALEN gene editing to generate isogenic DR4/DR5 knockout cells; Co-immunoprecipitation of DR4 with FADD/caspase-8 during ER stress; calcium flux assays; apoptosis assays with thapsigargin/tunicamycin/brefeldin A; motility/invasion assays Oncotarget High 28039489
2000 Homozygous deletion of DR4 encompassing its death domain in the FaDu nasopharyngeal cancer cell line confers TRAIL resistance; reintroduction of wild-type DR4 restores TRAIL sensitivity and induces apoptosis, demonstrating that the DR4 death domain is required for TRAIL-induced apoptotic signaling. Loss-of-heterozygosity/genomic deletion analysis; wild-type DR4 reconstitution by transfection; TRAIL cytotoxicity assays International journal of oncology High 10762627
2021 DR4 undergoes constitutive clathrin-dependent and -independent endocytosis and recycling back to the plasma membrane independently of TRAIL sensitivity. Inhibition of endocytosis (with sucrose) sensitizes resistant cells to TRAIL and increases cytotoxicity in sensitive cells, indicating that endocytosis negatively regulates TRAIL-DR4 surface signaling. Live-cell flow cytometry tracking receptor internalization and recycling; receptor-selective TRAIL variant (DR5-B) to show DR5 internalizes independently of DR4; cycloheximide/brefeldin A to distinguish new synthesis from recycling; sucrose-mediated endocytosis inhibition with TRAIL cytotoxicity readout Frontiers in cell and developmental biology High 34660590
2011 DR4 and DR5 redistribution into lipid rafts upon TRAIL treatment occurs in TRAIL-sensitive (H460) but not in TRAIL-resistant (A549) NSCLC cells; DR4 total expression level does not correlate with TRAIL sensitivity. Lipid raft disruption with nystatin abolishes sensitivity, and DR4 siRNA knockdown in sensitive cells does not affect TRAIL-induced apoptosis capacity, implicating that raft-localized DR4/DR5 rather than total DR4 expression drives sensitivity. Sucrose density gradient fractionation of lipid rafts; siRNA knockdown of DR4; nystatin treatment; TRAIL apoptosis assays International journal of oncology Medium 21769428
2012 DR4 and DR5 mediate oligomeric Aβ-induced extrinsic apoptosis in human cerebral microvascular endothelial cells: oligomeric Aβ directly binds DR4 and DR5 chimeric fusion proteins, upregulates their expression, and RNA silencing of both receptors protects against Aβ-induced caspase-8 and caspase-9 activation and Bid cleavage. Direct binding assay using receptor chimeras; RNA silencing of DR4 and DR5; caspase-8/9 activation assays; Bid cleavage assay; immunofluorescence co-localization Cell death & disease Medium 22695614
2009 Valproic acid (a histone deacetylase inhibitor) causes redistribution of DR4 into plasma membrane lipid rafts in U266 myeloma cells, restoring DR4 signaling and overcoming TRAIL resistance; membrane expression level of DR4 (not total expression) and caspase-8 expression levels, but not Mcl-1 intracellular levels, predict myeloma cell sensitivity to TRAIL. Lipid raft fractionation; flow cytometry for membrane DR4; siRNA for caspase-8 and DR4/DR5; Mcl-1 overexpression; TRAIL apoptosis assays Experimental cell research Medium 17462628
2005 Epigenetic silencing of DR4 via promoter hypermethylation underlies TRAIL resistance in ovarian cancer cells; demethylation with 5-aza-2'-deoxycytidine or transient DR4 transfection restores TRAIL sensitivity in the TRAIL-resistant A2780 cell line. Methylation-specific PCR; 5-aza-2'-deoxycytidine demethylation treatment; transient DR4 transfection; TRAIL apoptosis assays Molecular cancer research : MCR Medium 15972852

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Safety and antitumor activity of recombinant soluble Apo2 ligand. The Journal of clinical investigation 1917 10411544
1997 Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 605 9430227
1997 TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 598 9430228
1986 Molecular diversity of HLA-DR4 haplotypes. Proceedings of the National Academy of Sciences of the United States of America 391 3458223
1991 Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 362 1944595
2004 Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene 241 15208660
2005 Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. The Journal of biological chemistry 227 16227629
2001 Differential secretion of Fas ligand- or APO2 ligand/TNF-related apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. Journal of immunology (Baltimore, Md. : 1950) 214 11739488
1999 Activated human T cells release bioactive Fas ligand and APO2 ligand in microvesicles. Journal of immunology (Baltimore, Md. : 1950) 210 10415024
1994 Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements. The EMBO journal 183 8137825
1998 APO2 ligand: a novel lethal weapon against malignant glioma? FEBS letters 167 9613612
1998 Involvement of APO2 ligand/TRAIL in activation-induced death of Jurkat and human peripheral blood T cells. European journal of immunology 167 9754559
1998 Dominant-negative FADD inhibits TNFR60-, Fas/Apo1- and TRAIL-R/Apo2-mediated cell death but not gene induction. Current biology : CB 142 9427646
2004 The fetoprotein transcription factor (FTF) gene is essential to embryogenesis and cholesterol homeostasis and is regulated by a DR4 element. The Journal of biological chemistry 137 15014077
1992 Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals. Nature genetics 123 1345171
2010 Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. Current opinion in cell biology 121 20813513
2005 Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer. Molecular cancer research : MCR 117 15972852
1999 Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4. The Journal of clinical investigation 115 10562307
2000 Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor 5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells. Cancer research 113 11059770
1997 Monitoring early cellular responses in apoptosis is aided by the mitochondrial membrane protein-specific monoclonal antibody APO2.7. Cytometry 112 9415413
2001 Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene. Journal of cellular physiology 110 11382926
2000 TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages. Journal of immunology (Baltimore, Md. : 1950) 108 10706675
2016 Apigenin potentiates TRAIL therapy of non-small cell lung cancer via upregulating DR4/DR5 expression in a p53-dependent manner. Scientific reports 96 27752089
2015 DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells. The Journal of biological chemistry 96 25770212
2000 Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance. International journal of oncology 95 10762627
2002 Sensitization of tumor cells to Apo2 ligand/TRAIL-induced apoptosis by inhibition of casein kinase II. Cancer research 93 12154014
2000 Lipopolysaccharide induces expression of APO2 ligand/TRAIL in human monocytes and macrophages. Scandinavian journal of immunology 82 10736093
1998 T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin. Proceedings of the National Academy of Sciences of the United States of America 82 9520453
1988 HLA-DR4 and other genetic markers in rheumatoid arthritis. British journal of rheumatology 82 3261186
2017 N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death. Cell death and differentiation 79 28186505
2009 Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling. The Biochemical journal 76 19090789
2002 IFN-beta pretreatment sensitizes human melanoma cells to TRAIL/Apo2 ligand-induced apoptosis. Journal of immunology (Baltimore, Md. : 1950) 76 12097388
1998 Expression of Fas-Fas ligand antigens and apoptotic marker APO2.7 by the human conjunctival epithelium. Positive correlation with class II HLA DR expression in inflammatory ocular surface disorders. Experimental eye research 74 9990333
2016 Cell death-independent activities of the death receptors CD95, TRAILR1, and TRAILR2. The FEBS journal 73 27865080
2012 TRAIL death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer's Aβ. Cell death & disease 73 22695614
2021 The LARGE2-APO1/APO2 regulatory module controls panicle size and grain number in rice. The Plant cell 69 33693937
2007 Chemotherapy-resistant side-population of colon cancer cells has a higher sensitivity to TRAIL than the non-SP, a higher expression of c-Myc and TRAIL-receptor DR4. Cancer biology & therapy 69 17881904
1995 Association between Vogt-Koyanagi-Harada syndrome and HLA-DR1 and -DR4 in Hispanic patients living in southern California. Ophthalmology 67 9121744
2017 Antibodies and Derivatives Targeting DR4 and DR5 for Cancer Therapy. Antibodies (Basel, Switzerland) 66 31548531
2004 Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL. Cancer research 66 15604280
2017 TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress. Oncotarget 65 28039489
2000 Genomic organization and transcriptional regulation of human Apo2/TRAIL gene. Biochemical and biophysical research communications 65 11095979
2006 Nitrosylcobalamin promotes cell death via S nitrosylation of Apo2L/TRAIL receptor DR4. Molecular and cellular biology 63 16847314
2012 Cell death via DR5, but not DR4, is regulated by p53 in myeloma cells. Cancer research 61 22738917
2009 Cross-recognition of HLA DR4 alloantigen by virus-specific CD8+ T cells: a new paradigm for self-/nonself-recognition. Blood 59 19617574
2006 Mcl-1L cleavage is involved in TRAIL-R1- and TRAIL-R2-mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells. Blood 57 16638930
2002 Tumor-infiltrating CD4+ T lymphocytes express APO2 ligand (APO2L)/TRAIL upon specific stimulation with autologous lung carcinoma cells: role of IFN-alpha on APO2L/TRAIL expression and -mediated cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 56 12097384
2012 Effects of polymorphisms in TRAILR1 and TNFR1A on the response to anti-TNF therapies in patients with rheumatoid and psoriatic arthritis. Joint bone spine 55 22480748
2015 Long non-coding RNA LOC389641 promotes progression of pancreatic ductal adenocarcinoma and increases cell invasion by regulating E-cadherin in a TNFRSF10A-related manner. Cancer letters 54 26708505
2009 HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy. Archives of pediatrics & adolescent medicine 54 19487610
1996 HLA-DR4 may determine expression of actinic prurigo in British patients. The Journal of investigative dermatology 54 8601742
2018 Proscillaridin A induces apoptosis and suppresses non-small-cell lung cancer tumor growth via calcium-induced DR4 upregulation. Cell death & disease 53 29899551
2012 MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma. BMC cancer 52 22672670
2000 Ligand-triggered stabilization of vitamin D receptor/retinoid X receptor heterodimer conformations on DR4-type response elements. Journal of molecular biology 52 10677278
2007 Membrane expression of DR4, DR5 and caspase-8 levels, but not Mcl-1, determine sensitivity of human myeloma cells to Apo2L/TRAIL. Experimental cell research 51 17462628
2003 Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene 50 14614459
2006 APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy. Frontiers in bioscience : a journal and virtual library 49 16368536
2002 Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes. European journal of immunology 49 11857340
2008 Bone marrow stroma confers resistance to Apo2 ligand/TRAIL in multiple myeloma in part by regulating c-FLIP. Journal of immunology (Baltimore, Md. : 1950) 47 18209050
1999 Expression of mitochondrial Apo2.7 molecules and caspase-3 activation in human lymphocytes treated with the ribosome-inhibiting mistletoe lectins and the cell membrane permeabilizing viscotoxins. Cytometry 47 10486525
2009 TRAIL-induced apoptosis and expression of death receptor TRAIL-R1 and TRAIL-R2 in bladder cancer cells. Folia histochemica et cytobiologica 46 20430723
1999 Control of apoptosis signaling by Apo2 ligand. Recent progress in hormone research 45 10548878
2010 GLI3-dependent repression of DR4 mediates hedgehog antagonism of TRAIL-induced apoptosis. Oncogene 44 20562908
2008 Death receptor-4 (DR4) expression is regulated by transcription factor NF-kappaB in response to etoposide treatment. Apoptosis : an international journal on programmed cell death 44 18421578
2002 Mannose-binding lectin variant alleles and HLA-DR4 alleles are associated with giant cell arteritis. The Journal of rheumatology 42 12375325
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1987 HLA-DR4 and Gm(1,3;5,21) are associated with U1-nRNP antibody positive connective tissue disease. Annals of the rheumatic diseases 41 2953314
1999 Sensitization of AIDS-Kaposi's sarcoma cells to Apo-2 ligand-induced apoptosis by actinomycin D. Journal of immunology (Baltimore, Md. : 1950) 40 10228045
2003 Enhancement of TRAIL/Apo2L-mediated apoptosis by adriamycin through inducing DR4 and DR5 in renal cell carcinoma cells. International journal of cancer 39 12584736
2003 Arsenic trioxide selectively induces early and extensive apoptosis via the APO2/caspase-8 pathway engaging the mitochondrial pathway in myeloma cells with mutant p53. Cell cycle (Georgetown, Tex.) 38 12851490
2009 Reactivation of death receptor 4 (DR4) expression sensitizes medulloblastoma cell lines to TRAIL. Journal of neuro-oncology 36 19148581
2021 Death Receptors DR4 and DR5 Undergo Spontaneous and Ligand-Mediated Endocytosis and Recycling Regardless of the Sensitivity of Cancer Cells to TRAIL. Frontiers in cell and developmental biology 35 34660590
2012 A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX. The EMBO journal 35 22246181
2004 Dissection of the HLA-DR4 peptide repertoire in endocrine epithelial cells: strong influence of invariant chain and HLA-DM expression on the nature of ligands. Journal of immunology (Baltimore, Md. : 1950) 35 15240697
2021 The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR. Science immunology 33 33863750
2012 Suppression of HSP70 expression sensitizes NSCLC cell lines to TRAIL-induced apoptosis by upregulating DR4 and DR5 and downregulating c-FLIP-L expressions. Journal of molecular medicine (Berlin, Germany) 33 22948392
1999 HLA associations in type 1 diabetes among patients not carrying high-risk DR3-DQ2 or DR4-DQ8 haplotypes. Tissue antigens 33 10674967
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2009 TRAIL, DR4 and DR5 are upregulated in kidneys from patients with lupus nephritis and exert proliferative and proinflammatory effects. Clinical immunology (Orlando, Fla.) 32 19349211
2002 Differential nuclear receptor signalling from DR4-type response elements. Journal of cellular biochemistry 32 12210766
2014 CD70-restricted specific activation of TRAILR1 or TRAILR2 using scFv-targeted TRAIL mutants. Cell death & disease 31 24481449
2004 Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase. International journal of oncology 31 15547696
2019 Benzyl Isothiocyanate Induces Apoptosis via Reactive Oxygen Species-Initiated Mitochondrial Dysfunction and DR4 and DR5 Death Receptor Activation in Gastric Adenocarcinoma Cells. Biomolecules 30 31817791
2007 S-phase checkpoints regulate Apo2 ligand/TRAIL and CPT-11-induced apoptosis of prostate cancer cells. Molecular cancer therapeutics 27 17431115
2012 Targeting TRAIL death receptor 4 with trivalent DR4 Atrimer complexes. Molecular cancer therapeutics 26 22802267
2011 Redistribution of DR4 and DR5 in lipid rafts accounts for the sensitivity to TRAIL in NSCLC cells. International journal of oncology 26 21769428
2000 CD59 cross-linking induces secretion of APO2 ligand in overactivated human T cells. European journal of immunology 26 10760796
1999 Induction of mitochondrial Apo2.7 molecules and generation of reactive oxygen-intermediates in cultured lymphocytes by the toxic proteins from Viscum album L. Cancer letters 26 10408913
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2020 Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death. Cell death & disease 25 32917855
2019 Short Panicle 3 controls panicle architecture by upregulating APO2/RFL and increasing cytokinin content in rice. Journal of integrative plant biology 25 30302902
2008 HLA-DM negatively regulates HLA-DR4-restricted collagen pathogenic peptide presentation and T cell recognition. European journal of immunology 25 18506881
2014 DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer. Cancer biology & therapy 24 25482930
2007 Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice. Journal of autoimmunity 24 17949947
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2019 Morin enhances auranofin anticancer activity by up-regulation of DR4 and DR5 and modulation of Bcl-2 through reactive oxygen species generation in Hep3B human hepatocellular carcinoma cells. Phytotherapy research : PTR 22 30887612
1997 The orphan nuclear receptor TR2 suppresses a DR4 hormone response element of the mouse CRABP-I gene promoter. Biochemistry 22 9369481
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