Affinage

CASP8

Caspase-8 · UniProt Q14790

Length
479 aa
Mass
55.4 kDa
Annotated
2026-06-09
100 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CASP8 is an initiator cysteine protease that serves as the apical enzymatic trigger of death receptor-induced apoptosis, recruited through its N-terminal death effector domains to FADD/MORT1 at the death-inducing signaling complex (DISC) of Fas/CD95 and TNF receptors (PMID:8681376, PMID:9184224). At the DISC, CASP8 is activated by a two-step autoproteolytic mechanism — an initial cleavage generating p43/p12 followed by release of the active-site p18 fragment — and this activation strictly requires DISC association and is blocked by IETD-type peptide inhibitors (PMID:9184224). Once active, recombinant CASP8 directly processes and activates the full set of downstream ICE/CED-3-family caspases (CASP3, CASP6, CASP7 and others) and is inhibited by the serpin CrmA, establishing it as the most upstream protease of the cascade (PMID:8962078, PMID:9006941); genetic loss in Jurkat cells abolishes Fas-induced apoptosis and downstream caspase and stress-kinase activation, confirming its essential apical role (PMID:9740801). CASP8 function is context-dependent: in drug-induced (mitochondrial) apoptosis it is not the initiator but acts as an amplifying executioner downstream of mitochondria and caspase-3 (PMID:10216102, PMID:11030145). Beyond apoptosis, CASP8 participates in non-death signaling — its prodomain interacts with RIP1 to drive NF-κB activation under control of the c-FLIP(L) C-terminal domain (PMID:24398693), an autocleaved DEDa prodomain fragment translocates to the nucleus to sustain CASP8 transcription via TOPORS/p53 (PMID:17290218), and active CASP8 cleaves the vesicular transport protein FYCO1 to modulate death receptor trafficking and TRAIL sensitivity (PMID:37418591). CASP8 levels are set transcriptionally by IRF1 and Sp1 and post-transcriptionally by ELAVL1-mediated mRNA stabilization (PMID:38319288, PMID:17450141). In the intestinal epithelium, constitutive low-level CASP8 activation controlled by cFLIP is required for homeostasis and barrier integrity, and its loss causes ileocolitis and barrier dysfunction (PMID:31411503, PMID:24036366).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Established the molecular identity of CASP8 and connected death receptor engagement to a proteolytic effector by showing it binds FADD via its prodomain and triggers cell death downstream of Fas and TNFR.

    Evidence Yeast two-hybrid cloning, co-immunoprecipitation, and overexpression-induced death assays

    PMID:8681376

    Open questions at the time
    • Did not define the activation mechanism or direct downstream substrates
    • Overexpression-driven death may not reflect endogenous kinetics
  2. 1996 High

    Defined CASP8 as a self-processing two-subunit enzyme and placed it atop the protease cascade by showing it directly cleaves all known ICE/CED-3 caspases in vitro and is blocked by CrmA.

    Evidence Bacterial recombinant enzyme, in vitro substrate cleavage, N-terminal sequencing, CrmA inhibition

    PMID:8962078

    Open questions at the time
    • In vitro substrate promiscuity may not reflect physiological selectivity
    • Did not address how activation is gated in cells
  3. 1997 High

    Resolved how CASP8 is activated in cells, showing a two-step DISC-localized cleavage requiring DED-mediated FADD binding, distinguishing receptor-proximal activation from cytosolic processing.

    Evidence DISC fractionation/immunoprecipitation, cleavage-site antibodies, peptide inhibitor and mass spectrometry studies

    PMID:9184224

    Open questions at the time
    • Structural basis of dimerization-induced activation not defined
    • Did not quantify proximity-induced versus autocatalytic contributions
  4. 1997 High

    Confirmed in a defined cell-free system that CASP8 directly initiates the downstream caspase cascade, consolidating its apical position.

    Evidence Cell-free reconstitution with recombinant FLICE and caspase zymogens plus CrmA inhibition

    PMID:9006941

    Open questions at the time
    • Did not establish which caspases are direct physiological substrates in vivo
  5. 1997 Medium

    Clarified which CASP8 isoforms operate physiologically, showing only caspase-8/a and /b are detectably expressed and are recruited to and activated at the DISC.

    Evidence Monoclonal antibody panel, western blotting, DISC immunoprecipitation, activation kinetics

    PMID:9341131

    Open questions at the time
    • Antibody detection from a single lab
    • Function of remaining isoforms unresolved
  6. 1998 High

    Provided genetic proof of essentiality, showing CASP8-deficient cells lose Fas apoptosis and downstream caspase/kinase activation, rescued by complementation.

    Evidence Caspase-8-deficient Jurkat line with wild-type complementation and pathway readouts

    PMID:9740801

    Open questions at the time
    • Did not separate apoptotic from non-apoptotic CASP8 requirements
    • Cell-line-specific epistasis
  7. 1999 High

    Revealed a receptor-independent activation context, showing anticancer drugs activate CASP8 without CD95 ligand engagement or functional FADD.

    Evidence CD95-resistant cells, dominant-negative FADD, p18 western blotting, inhibitor studies

    PMID:10216102

    Open questions at the time
    • Did not define whether CASP8 was initiator or amplifier in this context
  8. 2000 High

    Reassigned CASP8's role in drug-induced apoptosis as an amplifying executioner downstream of mitochondria and caspase-3 rather than the initiator.

    Evidence CASP8-deficient Jurkat, Bcl-xL overexpression, dominant-negative caspase-9, caspase-3-null MCF7 reconstitution

    PMID:11030145

    Open questions at the time
    • Molecular trigger of CASP8 cleavage downstream of caspase-3 not detailed
  9. 2002 Medium

    Enabled in situ monitoring of CASP8 and FLIP cleavage and linked CASP8 processing to differentiation-dependent Fas sensitivity.

    Evidence Cleavage-site-directed antibodies, immunoblotting, flow cytometry, in vitro GST-FLIP cleavage

    PMID:12097160

    Open questions at the time
    • Single-lab antibody reagents
    • Mechanism linking differentiation to Fas resistance not fully defined
  10. 2007 Medium

    Uncovered a non-apoptotic transcriptional feedback role, showing an autocleaved DEDa prodomain fragment enters the nucleus and sustains CASP8 expression via TOPORS/p53.

    Evidence In vitro cleavage, co-IP, nuclear fractionation, ERK1/2 RNAi, reporter assays, confocal microscopy

    PMID:17290218

    Open questions at the time
    • Single-lab mechanism
    • Physiological significance of the feedback loop in vivo unclear
  11. 2007 Medium

    Established a functional promoter variant controlling CASP8 expression, showing a 6N deletion disrupting an Sp1 site lowers transcription, caspase-8 activity, and activation-induced T-cell death.

    Evidence Promoter reporter assays, Sp1 site analysis, caspase activity in carrier lymphocytes, case-control genotyping

    PMID:17450141

    Open questions at the time
    • Causal disease link beyond association not established here
  12. 2013 High

    Defined a homeostatic survival role, showing cFLIP-controlled constitutive low-level CASP8 activation sustains intestinal epithelium and that cFLIP loss causes fatal CASP8/CASP3-dependent apoptosis requiring death receptor ligands.

    Evidence Inducible and permanent epithelial cFlip knockout mice, caspase activity assays, ligand neutralization

    PMID:24036366

    Open questions at the time
    • Molecular basis distinguishing survival from death-inducing CASP8 activation unresolved
  13. 2019 Medium

    Demonstrated an intrinsic epithelial requirement for CASP8 in barrier integrity, with epithelial deletion causing ileocolitis and reduced Muc2/defensin expression.

    Evidence Intestinal epithelial-specific CASP8 knockout mice, histology, endoscopy, barrier gene expression

    PMID:31411503

    Open questions at the time
    • Mechanism linking CASP8 loss to mucin/defensin reduction not defined
    • Single lab
  14. 2021 Medium

    Linked CASP8 to anti-tumor immunity by showing it drives PD-L1 degradation via A20 (TNFAIP3) upregulation, with knockdown raising PD-L1 and promoting immune-dependent tumor growth.

    Evidence shRNA knockdown in melanoma, in vivo tumor assays, PD-L1 ubiquitination assays, NK-cell-specific conditional knockout

    PMID:33934451

    Open questions at the time
    • Whether protease activity or scaffolding drives A20 upregulation unclear
    • Single lab
  15. 2023 High

    Identified FYCO1 as a direct CASP8 substrate, showing cleavage at D1306 inactivates vesicular transport and modulates DISC stability and TRAIL receptor trafficking.

    Evidence Affinity purification, in vitro cleavage with D1306 mutagenesis, CRISPR/shRNA knockout, DISC IP, receptor trafficking assays

    PMID:37418591

    Open questions at the time
    • Generality of FYCO1 cleavage across cell types not established
  16. 2024 Medium

    Defined dual regulation of CASP8 abundance, showing IRF1-driven transcription and ELAVL1-mediated mRNA stabilization are required for death receptor-initiated apoptosis.

    Evidence Genetic screen, RNA-IP, IRF1 ChIP, mRNA stability assays, ELAVL1 knockout, caspase/death assays

    PMID:38319288

    Open questions at the time
    • Interplay between transcriptional and post-transcriptional control not quantified
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same enzyme switches between constitutive survival signaling, non-apoptotic NF-κB/transcriptional roles, and full apoptotic execution at the molecular level remains unresolved.
  • No unified structural/biochemical switch defined for survival versus death outputs
  • In vivo substrate repertoire beyond caspases, Bid, FYCO1, and FLIP incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
CFLARELAVL1FADDFYCO1RIP1TOPORS
Complex memberships
DISC

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CASP8 (MACH/FLICE) was cloned as a novel protein that binds MORT1/FADD via its prodomain and contains an ICE/CED-3-like protease domain. Cellular expression of proteolytic MACH isoforms causes cell death downstream of Fas/APO-1 and p55-TNF receptor, establishing CASP8 as the most upstream enzymatic component in death receptor-induced apoptosis cascades. Yeast two-hybrid cloning, co-immunoprecipitation, cellular overexpression assays Cell High 8681376
1996 Recombinant Mch5/CASP8 (MACH/FLICE) is a mature two-subunit enzyme generated by autocleavage at Asp-227, Asp-233, Asp-391, and Asp-401. It directly processes and activates all known ICE/CED-3-like cysteine proteases (CPP32, Mch2, Mch3, Mch4, Mch6, ICE, TX, ICErelIII, ICH-1) and is potently inhibited by the cowpox serpin CrmA, placing it as the most upstream Fas-pathway protease. Bacterial recombinant expression, in vitro protease activity assays, N-terminal sequencing of cleavage products, CrmA inhibition assays Proceedings of the National Academy of Sciences of the United States of America High 8962078
1997 CASP8/FLICE is activated at the CD95 (Fas/APO-1) DISC by a two-step proteolytic mechanism: initial cleavage generates p43 and p12 fragments; subsequent cleavage of receptor-bound p43 releases the active-site-containing p18 fragment and prodomain p26. Activation requires association with the DISC (mediated by N-terminal DED binding to FADD) and is blocked by zVAD-fmk, zDEVD-fmk, and zIETD-fmk but not by CrmA or Ac-YVAD-CHO. Biochemical fractionation, immunoprecipitation of DISC components, western blot with cleavage-site antibodies, peptide inhibitor studies, mass spectrometry identification of DISC proteins The EMBO journal High 9184224
1997 Recombinant FLICE/CASP8 directly activates downstream caspase zymogens in a cell-free system; CrmA attenuates this activation, consistent with CASP8 being the apical triggering protease in the CD95/TNFR-1-initiated caspase cascade. Cell-free system reconstitution, recombinant FLICE incubation with caspase zymogens, CrmA inhibition The Journal of biological chemistry High 9006941
1997 Among eight described CASP8 isoforms, only caspase-8/a and caspase-8/b are detectably expressed at the protein level in cells of diverse origin. Both isoforms are recruited to the CD95 DISC and activated upon CD95 stimulation with similar kinetics. Monoclonal antibody panel generation, western blotting, immunoprecipitation of DISC, kinetics of activation assays The Journal of biological chemistry Medium 9341131
1998 Genetic complementation of a caspase-8-deficient Jurkat cell line demonstrates that CASP8 is essential and apical in the Fas-induced apoptotic cascade. Loss of CASP8 completely abrogates Fas-induced apoptosis and blocks activation of multiple downstream caspases as well as stress kinases p38 and JNK. The deficient line is also severely impaired in TNF-α-induced cell death. Genetic screen, isolation of caspase-8-deficient cell line, complementation with wild-type CASP8, caspase activity assays, kinase activation assays Current biology : CB High 9740801
1999 Anticancer drugs (daunorubicin, doxorubicin, etoposide, mitomycin C, cycloheximide) activate CASP8 in Jurkat cells independently of CD95 receptor/ligand interaction, as shown by equal drug-induced CASP8 activation in CD95-resistant cells and by failure of dominant-negative FADD (which blocks CD95 signaling) to prevent drug-induced CASP8 cleavage to its active p18 subunit. CD95-resistant cell lines, dominant-negative FADD overexpression, western blot for caspase-8 p18 fragment, caspase inhibitor studies Blood High 10216102
2000 In the mitochondrial (drug-induced) apoptosis pathway, CASP8 acts as an amplifying executioner caspase downstream of the mitochondria, not as the initiating protease. Anticancer drugs still process caspase-9, -3, and Bid in CASP8-deficient Jurkat cells; Bcl-xL overexpression or dominant-negative caspase-9 blocks drug-induced CASP8 processing; in caspase-3-lacking MCF7 cells, CASP8 is not activated by drugs unless caspase-3 is restored by transfection. Caspase-8-deficient Jurkat cells, Bcl-xL overexpression, dominant-negative caspase-9, caspase-3-lacking MCF7 cells with caspase-3 transfection, western blotting Oncogene High 11030145
2007 The CASP8 prodomain can be autocleavaged between its two tandem DEDs (at Asp129 by caspase-8 itself), generating a DEDa fragment. DEDa translocates to the nucleus via association with ERK1/2, interacts with TOPORS (a p53/topoisomerase I binding protein), and displaces p53 from TOPORS to allow p53-mediated stimulation of CASP8 gene expression, forming a positive feedback loop during apoptosis. In vitro cleavage assay, co-immunoprecipitation, nuclear fractionation, RNA interference of ERK1/2, reporter assays, confocal microscopy The EMBO journal Medium 17290218
2014 The C-terminal domain of c-FLIP(L) specifically inhibits the interaction of the CASP8 prodomain with the RIP1 death domain, thereby regulating CASP8-dependent NF-κB activation induced by FasL. The prodomain of CASP8 is sufficient to interact with RIP1 and to mediate NF-κB activation; c-FLIP(p43) (lacking the C-terminal domain) does not inhibit this interaction. Co-immunoprecipitation, mutant c-FLIP constructs (c-FLIPD376N, c-FLIPp43), HEK 293 cells lacking caspase-8, caspase inhibitor (zVAD), NF-κB reporter assays The Journal of biological chemistry Medium 24398693
2021 CASP8 induces PD-L1 degradation by upregulating TNFAIP3 (A20), a ubiquitin-editing enzyme that promotes PD-L1 ubiquitination. Knockdown of CASP8 in melanoma cells increases PD-L1 levels and promotes tumor progression in an immune system-dependent manner. shRNA knockdown of CASP8 in mouse melanoma cells, in vivo tumor growth assays, western blot/ubiquitination assays for PD-L1, conditional NK-cell-specific CASP8 knockout mice (Ncr1iCre/+ Casp8fl/fl) Cancer science Medium 33934451
2024 TNF/IFNγ-induced CASP8 activation and cancer cell death require IRF1-mediated transcriptional upregulation of CASP8 (and CYLD). Additionally, ELAVL1 (HuR) binds CASP8 mRNA and stabilizes it under both basal and IFNγ-stimulated conditions; loss of ELAVL1 reduces CASP8 levels and blocks death receptor-initiated caspase-8-dependent apoptosis (from TNF, TRAIL, and FasL). Genetic screen, RNA immunoprecipitation (ELAVL1-CASP8 mRNA binding), IRF1 ChIP/transcription assays, mRNA stability assays, genetic KO of ELAVL1, caspase activity assays, cancer cell death assays The Journal of cell biology Medium 38319288
2023 FYCO1 (an autophagic vesicle transport protein) is a direct substrate of activated CASP8. CASP8 cleaves FYCO1 at aspartate 1306, releasing the C-terminal GOLD domain and inactivating FYCO1 function. Loss of FYCO1 sensitizes cells to TRAIL-induced apoptosis by stabilizing the DISC and impairing TNFRSF10B (TRAIL-R2/DR5) transport to lysosomes. Affinity purification/co-immunoprecipitation with activated CASP8, in vitro cleavage assay with mutagenesis of cleavage site (D1306), CRISPR/shRNA KO of FYCO1, DISC immunoprecipitation, receptor trafficking assays Autophagy High 37418591
2019 Deletion of epithelial Casp8 in mice (Casp8∆IEC) results in ileocolitis, epithelial barrier dysfunction, reduced expression of Muc2 and defensins, and impaired body weight gain, establishing a required role for CASP8 in intestinal epithelial homeostasis. The intestinal phenotype is consistent with earlier work showing cFlip-regulated constitutive CASP8 activation. Conditional intestinal epithelial-specific CASP8 knockout mice, histology, endoscopy, gene expression analysis of barrier genes American journal of physiology. Gastrointestinal and liver physiology Medium 31411503
2013 cFlip expression in intestinal epithelial cells is required for constitutive low-level activation of caspase-8 under steady-state conditions, which promotes cell survival. Conditional deletion of cFlip in adult intestinal epithelium leads to massive CASP8- and CASP3-dependent apoptosis and fatal intestinal destruction within days; cell death requires death receptor ligands (TNF-α, CD95L) and is independent of RIP3. Conditional (inducible and permanent) intestinal epithelial knockout of cFlip, caspase-8 and caspase-3 activity assays, histology, death receptor ligand neutralization experiments Gastroenterology High 24036366
2007 A 6-nucleotide deletion in the CASP8 promoter (-652 6N del) destroys an Sp1 binding site, decreases CASP8 transcription, and results in lower caspase-8 activity and reduced activation-induced T-cell death in response to cancer cell antigens. Promoter reporter assay, Sp1 binding site analysis, biochemical caspase-8 activity measurement in T lymphocytes from variant carriers, case-control genotyping Nature genetics Medium 17450141
2002 Cleavage-site-directed antibodies demonstrate that CASP8/FLICE cleavage at the DISC and subsequent cleavage of its substrate FLIP (at LEVD376↓G) can be monitored in situ. Fas stimulation in IFN-γ-treated U937 cells markedly increases CASP8 processing; vitamin D3- or retinoic acid-differentiated Fas-resistant U937 cells show inhibited CASP8 processing, placing CASP8 activation upstream of changes in Fas sensitivity. Cleavage-site-directed antibodies, immunoblotting, flow cytometry, confocal microscopy, in vitro cleavage assays with GST-FLIP Journal of biochemistry Medium 12097160

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2266 19446902
1996 Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 2050 8681376
2000 Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet (London, England) 1846 10768432
1997 FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). The EMBO journal 1023 9184224
1996 Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proceedings of the National Academy of Sciences of the United States of America 489 8962078
1998 Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Current biology : CB 452 9740801
2011 Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 444 21684027
1997 I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. The Journal of biological chemistry 369 9211860
1997 FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. The Journal of biological chemistry 356 9341131
1999 The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. The Journal of experimental medicine 339 10510092
1997 FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. The Journal of biological chemistry 305 9006941
2021 Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 279 33515668
1999 Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein. The Journal of experimental medicine 275 10510093
1999 Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction. Blood 268 10216102
1997 A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma. The Journal of experimental medicine 252 9271594
2000 Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis. Oncogene 226 11030145
2007 A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nature genetics 219 17450141
2002 The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. The Journal of biological chemistry 202 11830587
2017 Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nature medicine 191 28218919
1999 Mistletoe lectin activates caspase-8/FLICE independently of death receptor signaling and enhances anticancer drug-induced apoptosis. Cancer research 176 10232592
2008 Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Current cancer drug targets 150 18288942
2006 Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets. Diabetes 138 17003335
2009 Cellular FLICE-inhibitory protein (c-FLIP) signalling: a key regulator of receptor-mediated apoptosis in physiologic context and in cancer. The international journal of biochemistry & cell biology 126 19932761
2003 Cellular FLICE/caspase-8-inhibitory protein as a principal regulator of cell death and survival in human hepatocellular carcinoma. Laboratory investigation; a journal of technical methods and pathology 120 12861043
2004 Possible role of FLICE-like inhibitory protein (FLIP) in chemoresistant ovarian cancer cells in vitro. Oncogene 115 15258564
2001 FLICE-inhibitory protein is a key regulator of germinal center B cell apoptosis. The Journal of experimental medicine 104 11181697
2012 Cellular FLICE-like inhibitory proteins (c-FLIPs): fine-tuners of life and death decisions. Experimental cell research 97 22309778
2003 The human herpes virus 8-encoded viral FLICE-inhibitory protein induces cellular transformation via NF-kappaB activation. The Journal of biological chemistry 94 14563855
2004 Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin's lymphoma cells from autonomous Fas-mediated death. Proceedings of the National Academy of Sciences of the United States of America 89 15096587
1998 ERICE, a novel FLICE-activatable caspase. The Journal of biological chemistry 89 9624166
2003 Cellular FLICE-inhibitory protein: an attractive therapeutic target? Expert opinion on therapeutic targets 87 12885274
2007 Methylation of CASP8, DCR2, and HIN-1 in neuroblastoma is associated with poor outcome. Clinical cancer research : an official journal of the American Association for Cancer Research 81 17545522
1999 Structure and chromosome localization of the human CASP8 gene. Gene 79 9931493
2011 Cellular FLICE-inhibitory protein (cFLIP) isoforms block CD95- and TRAIL death receptor-induced gene induction irrespective of processing of caspase-8 or cFLIP in the death-inducing signaling complex. The Journal of biological chemistry 78 21454681
2010 BCL2 and CASP8 regulation by NF-kappaB differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and -resistant breast cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 74 20154269
2005 Cellular FLICE-inhibitory protein is required for T cell survival and cycling. The Journal of experimental medicine 74 16043518
2001 Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2. Cancer research 74 11406564
2010 MULTICOM: a multi-level combination approach to protein structure prediction and its assessments in CASP8. Bioinformatics (Oxford, England) 72 20150411
2002 The human herpes virus 8-encoded viral FLICE inhibitory protein protects against growth factor withdrawal-induced apoptosis via NF-kappa B activation. Blood 67 12406869
2013 Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. Gastroenterology 66 24036366
2006 Cellular FLICE-inhibitory protein down-regulation contributes to celecoxib-induced apoptosis in human lung cancer cells. Cancer research 65 17145853
2004 FLICE/caspase-8 activation triggers anoikis induced by beta1-integrin blockade in human keratinocytes. Journal of cell science 65 15507484
2009 The other 90% of the protein: assessment beyond the Calphas for CASP8 template-based and high-accuracy models. Proteins 64 19731372
2001 Fas-associated death domain protein (FADD) and caspase-8 mediate up-regulation of c-Fos by Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via a FLICE inhibitory protein (FLIP)-regulated pathway. The Journal of biological chemistry 63 11384965
2000 Regulation of the Fas death pathway by FLICE-inhibitory protein in primary human B cells. Journal of immunology (Baltimore, Md. : 1950) 60 10975811
2001 Characterization of the human FLICE-inhibitory protein locus and comparison of the anti-apoptotic activity of four different flip isoforms. Scandinavian journal of immunology 59 11439165
2005 Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas. Endocrine-related cancer 55 15788647
2000 Expression of cellular FLICE-inhibitory protein in human coronary arteries and in a rat vascular injury model. The American journal of pathology 54 10623660
2012 MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma. BMC cancer 52 22672670
2011 Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction. Basic research in cardiology 48 22202974
2012 Cellular FLICE-like inhibitory protein deviates myofibroblast fas-induced apoptosis toward proliferation during lung fibrosis. American journal of respiratory cell and molecular biology 46 22582174
2012 Targeting c-FLICE-like inhibitory protein (CFLAR) in cancer. Expert opinion on therapeutic targets 46 23252466
2006 Cellular FLICE-like inhibitory protein (c-FLIP): a novel target for Taxol-induced apoptosis. Biochemical pharmacology 46 16579975
2006 Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma. BMC cancer 46 17064406
2014 The C-terminal domain of the long form of cellular FLICE-inhibitory protein (c-FLIPL) inhibits the interaction of the caspase 8 prodomain with the receptor-interacting protein 1 (RIP1) death domain and regulates caspase 8-dependent nuclear factor κB (NF-κB) activation. The Journal of biological chemistry 44 24398693
2003 Molecular genetic analysis of human herpes virus 8-encoded viral FLICE inhibitory protein-induced NF-kappaB activation. The Journal of biological chemistry 43 14561765
2006 The role of cellular FLICE inhibitory protein (c-FLIP) in the pathogenesis and treatment of cancer. Expert opinion on therapeutic targets 42 16441226
2019 Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/RelA, NF-κB activation, and promotion of cell invasion and angiogenesis. Cell death and differentiation 40 30670829
2020 Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis. Nature communications 39 32792491
2004 FLICE-like inhibitory protein (FLIP) protects against apoptosis and suppresses NF-kappaB activation induced by bacterial lipopolysaccharide. The American journal of pathology 39 15466406
2014 Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk. Human molecular genetics 38 25168388
2010 CASP8 polymorphisms contribute to cancer susceptibility: evidence from a meta-analysis of 23 publications with 55 individual studies. Carcinogenesis 36 20176653
2009 Coding polymorphisms in Casp5, Casp8 and DR4 genes may play a role in predisposition to lung cancer. Cancer letters 35 19203830
2021 Casp8 acts through A20 to inhibit PD-L1 expression: The mechanism and its implication in immunotherapy. Cancer science 33 33934451
2010 The six-nucleotide deletion/insertion variant in the CASP8 promoter region is inversely associated with risk of squamous cell carcinoma of the head and neck. Cancer prevention research (Philadelphia, Pa.) 31 20086182
2010 Cellular FLICE-inhibitory protein protects against cardiac remodeling induced by angiotensin II in mice. Hypertension (Dallas, Tex. : 1979) 31 20975036
2010 Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 31 20978178
2011 Polymorphisms in the CASP8 gene and the risk of epithelial ovarian cancer. Gynecologic oncology 30 21714991
2009 Target domain definition and classification in CASP8. Proteins 29 19603487
2007 Expression of cellular FLICE inhibitory protein, caspase-8, and protease inhibitor-9 in Ewing sarcoma and implications for susceptibility to cytotoxic pathways. Clinical cancer research : an official journal of the American Association for Cancer Research 28 17200356
2009 Methylation patterns of Rb1 and Casp-8 promoters and their impact on their expression in bladder cancer. Cancer investigation 26 19160091
2016 Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer. Human molecular genetics 25 26740556
2009 Protein structure prediction center in CASP8. Proteins 25 19722263
2000 Enhanced expression of Fas-associated death domain-like IL-1-converting enzyme (FLICE)-inhibitory protein induces resistance to Fas-mediated apoptosis in activated mast cells. Journal of immunology (Baltimore, Md. : 1950) 25 11086061
2007 Death effector domain DEDa, a self-cleaved product of caspase-8/Mch5, translocates to the nucleus by binding to ERK1/2 and upregulates procaspase-8 expression via a p53-dependent mechanism. The EMBO journal 24 17290218
2005 Expression of cellular FLICE/caspase-8 inhibitory protein is associated with malignant potential in endometrial carcinoma. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 24 16014121
2003 Long form of cellular FLICE-inhibitory protein interacts with Daxx and prevents Fas-induced JNK activation. Biochemical and biophysical research communications 24 14637155
2014 Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation. Molecular medicine reports 23 25333816
2012 shRNA mediated RHOXF1 silencing influences expression of BCL2 but not CASP8 in MCF-7 and MDA-MB-231 cell lines. Asian Pacific journal of cancer prevention : APJCP 23 23317270
2011 Fine-mapping CASP8 risk variants in breast cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 23 22056502
2021 Resveratrol promotes skin wound healing by regulating the miR-212/CASP8 axis. Laboratory investigation; a journal of technical methods and pathology 22 34234270
2009 Analysis of CASP8 targets, predictions and assessment methods. Database : the journal of biological databases and curation 22 20157476
2021 Discovery of CASP8 as a potential biomarker for high-risk prostate cancer through a high-multiplex immunoassay. Scientific reports 21 33828176
2018 Suppressed translation as a mechanism of initiation of CASP8 (caspase 8)-dependent apoptosis in autophagy-deficient NSCLC cells under nutrient limitation. Autophagy 21 29165042
2013 ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis. Journal of molecular medicine (Berlin, Germany) 21 23371318
2011 Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells. European journal of cancer (Oxford, England : 1990) 21 21726997
2023 Rosmarinic acid decreases viability, inhibits migration and modulates expression of apoptosis-related CASP8/CASP3/NLRP3 genes in human metastatic melanoma cells. Chemico-biological interactions 20 36863647
2020 Association of CASP8 polymorphisms and cancer susceptibility: A meta-analysis. European journal of pharmacology 20 32442541
2008 Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein. Cardiovascular therapeutics 20 18466417
2017 MiR-150 deficiency ameliorated hepatosteatosis and insulin resistance in nonalcoholic fatty liver disease via targeting CASP8 and FADD-like apoptosis regulator. Biochemical and biophysical research communications 19 29107687
2012 Association between CASP8 and CASP10 polymorphisms and toxicity outcomes with platinum-based chemotherapy in Chinese patients with non-small cell lung cancer. The oncologist 19 22843554
2005 Expression of cellular FLICE-inhibitory protein and its association with p53 mutation in colon cancer. World journal of gastroenterology 19 15832422
2024 TNF and IFNγ-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression. The Journal of cell biology 18 38319288
2023 Medicarpin suppresses proliferation and triggeres apoptosis by upregulation of BID, BAX, CASP3, CASP8, and CYCS in glioblastoma. Chemical biology & drug design 18 37515387
2019 Deletion of the Casp8 gene in mice results in ileocolitis, gut barrier dysfunction, and malassimilation, which can be partially attenuated by inulin or sodium butyrate. American journal of physiology. Gastrointestinal and liver physiology 18 31411503
2023 Apoptosis-targeted gene therapy for non-small cell lung cancer using chitosan-poly-lactic-co-glycolic acid -based nano-delivery system and CASP8 and miRs 29A-B1 and 34A. Frontiers in bioengineering and biotechnology 17 37346791
2023 The autophagic protein FYCO1 controls TNFRSF10/TRAIL receptor induced apoptosis and is inactivated by CASP8 (caspase 8). Autophagy 17 37418591
2013 The CASP8 -652 6N insertion/deletion promoter polymorphism is associated with renal cell carcinoma risk and metastasis. The Journal of urology 17 23313206
2007 CASP8 polymorphisms, estrogen and progesterone receptor status, and breast cancer risk. Breast cancer research and treatment 17 17940865
2002 Monitoring of caspase-8/FLICE processing and activation upon Fas stimulation with novel antibodies directed against a cleavage site for caspase-8 and its substrate, FLICE-like inhibitory protein (FLIP). Journal of biochemistry 17 12097160

Missed literature

Know a paper Affinage missed for CASP8? Flag it for the maintainers and the community.

No submissions yet.