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Showing APAF1 — APAF-1 is a alias.

APAF1

Apoptotic protease-activating factor 1 · UniProt O14727

Length
1248 aa
Mass
141.8 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 33 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

APAF-1 is the central scaffold of the mitochondrial (intrinsic) apoptosis pathway, a ~130 kDa protein that couples cytochrome c release to caspase activation and is essential in vivo for developmental apoptosis and normal brain morphogenesis (PMID:9267021, PMID:9753321, PMID:9753320). In its autoinhibited monomeric state the C-terminal WD40 β-propellers fold back onto the N-terminal CED-4-homologous region; binding of cytochrome c to the WD40 repeats relieves this autoinhibition, and exchange of ADP for dATP/ATP drives a large conformational change and self-association into a heptameric apoptosome (PMID:9837928, PMID:10393175, PMID:26543158, PMID:23521171). Deletion of the WD40 repeats yields a constitutively active, cytochrome c-independent scaffold, confirming their autoinhibitory role (PMID:9651578, PMID:9837928, PMID:10393175). The assembled apoptosome presents a central CARD–CARD disk that recruits procaspase-9, generating a holoenzyme in which caspase-9 is the catalytic subunit and APAF-1 acts as an allosteric activator that raises caspase-9 activity by orders of magnitude (PMID:10206961, PMID:10617566, PMID:23521171); activated caspase-9 then recruits and processes caspase-3 to execute death (PMID:11230124). APAF-1 activity is controlled at every level: assembly is blocked by Hsp70 binding the CARD, by PKA- and Rsk/14-3-3ε-dependent phosphorylation that prevents procaspase-9 recruitment, and by Bcl-2-family and CARD-binding inhibitors; signaling is terminated by caspase-3 cleavage that removes part of the CARD (PMID:10934466, PMID:10934467, PMID:11387322, PMID:15703181, PMID:22246185, PMID:9539746, PMID:9488720). APAF1 expression is itself a transcriptional readout of the p53/E2F1 and HDAC2/chromatin axes and is translated through an IRES in its 5'UTR, explaining its loss in mature neurons and cardiomyocytes that thereby become resistant to cytochrome c (PMID:11389439, PMID:11559530, PMID:18834886, PMID:18056406, PMID:10702798, PMID:12934072). Beyond apoptosis, APAF-1 has non-apoptotic roles: it undergoes ATR/Nup107-dependent nuclear translocation after DNA damage to promote Chk1 activation and cell-cycle arrest, and it regulates centrosome maturation by recruiting HCA66 (PMID:18042457, PMID:25695197, PMID:21984814).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Identifying the cytosolic factor that links cytochrome c to caspase-3 established the molecular core of the intrinsic apoptosis pathway.

    Evidence Protein purification from HeLa cytosol, cDNA cloning, and cell-free caspase activation

    PMID:9267021

    Open questions at the time
    • Did not resolve oligomeric state or nucleotide requirement
    • WD40 function only inferred from sequence
  2. 1998 High

    Reconstitution with purified components defined the biochemical logic of apoptosome assembly: nucleotide hydrolysis and cytochrome c drive oligomerization and stoichiometric procaspase-9 recruitment.

    Evidence In vitro reconstitution, gel filtration, ATPase assays, and deletion/P-loop mutagenesis with recombinant APAF-1 and procaspase-9

    PMID:10206961 PMID:10393175 PMID:9651578 PMID:9837928

    Open questions at the time
    • Atomic architecture of the oligomer not yet resolved
    • Mechanism of caspase-9 autocatalysis within the complex defined only functionally
  3. 1998 High

    Genetic ablation in mice proved APAF-1 is required for mitochondrial-pathway apoptosis in vivo and during neural development, while showing the death-receptor pathway is independent of it.

    Evidence Apaf1 knockout mice with developmental and caspase-processing phenotypes

    PMID:9753320 PMID:9753321

    Open questions at the time
    • Did not address non-apoptotic functions later attributed to APAF-1
    • Tissue-specific regulation not examined
  4. 1999 High

    Quantifying caspase-9 activity free versus APAF-1-bound established APAF-1 as an allosteric activator rather than a passive scaffold.

    Evidence Comparative enzymatic activity assays in a cell-free system

    PMID:10617566

    Open questions at the time
    • Structural basis of allostery not defined
    • Did not address downstream caspase-3 recruitment kinetics
  5. 2000 High

    Discovery that Hsp70 binds the APAF-1 CARD to block procaspase-9 loading defined a chaperone-based checkpoint distinct from oligomerization.

    Evidence Cell-free apoptosis systems and co-IP from two independent labs

    PMID:10934466 PMID:10934467

    Open questions at the time
    • Physiological conditions favoring Hsp70 inhibition in vivo not defined
  6. 2000 Medium

    IRES-dependent translation of APAF1 mRNA showed its synthesis can proceed independently of cap-dependent translation, providing a post-transcriptional control point.

    Evidence Bicistronic reporter assays with deletion mapping across cell lines

    PMID:10702798

    Open questions at the time
    • Trans-acting IRES regulators not identified in this study
    • Physiological triggers of IRES use not defined
  7. 2001 High

    Defining caspase-3 recruitment via a caspase-9 active-site interaction and XIAP-mediated inhibition placed downstream execution and its restraint within the apoptosome itself.

    Evidence Cell-free system with cytochrome c/dATP-activated lysates and mutational analysis

    PMID:11230124

    Open questions at the time
    • Quantitative stoichiometry of caspase-3 within the complex not resolved here
  8. 2001 High

    Establishing APAF1 as a direct E2F1 and p53 transcriptional target connected RB-pathway deregulation and DNA-damage signaling to apoptotic competence.

    Evidence ChIP, reporter and promoter binding assays, microarray with isogenic lines

    PMID:11389439 PMID:11559530

    Open questions at the time
    • Did not address chromatin-level repression mechanisms identified later
  9. 2001 High

    Identifying caspase-3 cleavage of APAF-1 that removes part of the CARD revealed a feedback mechanism that terminates apoptosome signaling.

    Evidence Cell-free cleavage with purified caspases, mass spectrometry, and gel filtration

    PMID:11387322

    Open questions at the time
    • In vivo timing and contribution of this cleavage to death outcomes not quantified
  10. 2004 High

    Immunopurification of native apoptosomes defined the in vivo composition (APAF-1, caspase-9, caspase-3, XIAP) and showed cytochrome c is not stably retained, plus identified Smac/DIABLO and PHAPI as activity modulators.

    Evidence One-step immunopurification, mass spectrometry, and in vitro activity assays

    PMID:15103327

    Open questions at the time
    • Did not establish stoichiometry of the native complex
    • Mechanism of PHAPI enhancement only partly defined
  11. 2005 High

    PKA was shown to suppress apoptosome formation by blocking cytochrome c-dependent procaspase-9 recruitment rather than by directly inactivating caspase-9, defining a cAMP-linked regulatory input.

    Evidence Xenopus and human cell-free assays, kinase assays, and site-directed mutagenesis

    PMID:15703181

    Open questions at the time
    • Direct PKA target on APAF-1 not identified
    • Physiological cAMP contexts not defined
  12. 2012 High

    Identifying Rsk phosphorylation of APAF-1 Ser268 that creates a 14-3-3ε docking site defined a growth-signaling route to apoptosome suppression and cytochrome c resistance.

    Evidence Kinase assay, phosphosite mutagenesis, co-IP, and cell-free apoptosis assay in cancer lines

    PMID:22246185

    Open questions at the time
    • In vivo prevalence of this modification across tissues not established
  13. 2007 High

    Demonstrating that APAF-1 drives DNA-damage-induced Chk1 activation and cell-cycle arrest, conserved through C. elegans ced-4, revealed a non-apoptotic checkpoint function.

    Evidence siRNA in human cells, Apaf-1 KO mouse cells, ced-4 mutants, and Chk1 epistasis

    PMID:18042457

    Open questions at the time
    • Molecular mechanism of nuclear import not yet defined at this stage
    • How APAF-1 promotes Chk1 activation mechanistically unresolved
  14. 2015 High

    Cryo-EM and crystallographic structures resolved the autoinhibition-release and assembly mechanism, showing cytochrome c binding to WD40 propellers and dATP-driven conformational change yield the heptameric apoptosome.

    Evidence 3.8 Å cryo-EM and full-length crystal structure with structure-guided mutagenesis

    PMID:23521171 PMID:26543158

    Open questions at the time
    • Dynamic intermediates of assembly not captured
    • Structure of the caspase-9-bound holoenzyme at high resolution incomplete
  15. 2015 Medium

    Identifying Nup107 as the ATR-regulated mediator of APAF-1 nuclear import mechanistically explained the DNA-damage checkpoint function.

    Evidence Co-IP, CED-4/Nup107 domain mapping, and dominant-negative interference with Chk1 readout

    PMID:25695197

    Open questions at the time
    • Single-lab study without reciprocal structural validation
    • Direct ATR phosphosite on APAF-1/Nup107 not pinpointed
  16. 2011 Medium

    Showing APAF-1 controls centrosome maturation via HCA66 recruitment established a death-independent role in spindle and cytoskeletal organization.

    Evidence siRNA, live imaging, immunofluorescence, co-IP, and migration/spindle assays

    PMID:21984814

    Open questions at the time
    • Single-lab study; in vivo relevance not tested
    • Mechanism by which APAF-1 directs HCA66 to centrosomes unresolved
  17. 2008 Medium

    Defining HDAC2 occupancy at the APAF1 promoter and neuronal chromatin state revealed epigenetic control that silences APAF1 in mature neurons, explaining cytochrome c resistance.

    Evidence ChIP, siRNA, stable knockdown, primary neuron cultures and E2F1/HDAC-inhibitor experiments

    PMID:18056406 PMID:18834886

    Open questions at the time
    • Full set of chromatin regulators not defined
    • Reversibility in disease contexts not established
  18. 2020 Medium

    Discovering an APAF-1/caspase-4 'pyroptosome' that routes through caspase-3 and GSDME extended APAF-1's scaffolding role to a non-canonical cell-death modality triggered by mitochondrial permeability transition.

    Evidence Co-IP, stoichiometry analysis, genetic knockouts, and caspase-cascade assays

    PMID:33308446

    Open questions at the time
    • Single-lab finding; structural basis of the 7:2 complex not resolved
    • Physiological and disease contexts of this pyroptosome unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (chaperones, phosphorylation, transcription, IRES translation, and non-apoptotic partners) are integrated to set apoptotic versus checkpoint versus pyroptotic outcomes in specific tissues remains unresolved.
  • No unified in vivo model integrating apoptotic and non-apoptotic APAF-1 functions
  • Tissue-specific weighting of regulatory mechanisms undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 3 GO:0060090 molecular adaptor activity 2 GO:0016787 hydrolase activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-1640170 Cell Cycle 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
BCL2L1CASP3CASP9CYCSHSPA1ANUP107XIAPYWHAE
Complex memberships
Apaf-1 pyroptosomeapoptosome

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Apaf-1 was purified from HeLa cell cytosol as a ~130 kDa protein that participates in cytochrome c-dependent activation of caspase-3. Cytochrome c binds to Apaf-1, and its NH2-terminal region shares homology with CED-3 prodomain and CED-4, while the C-terminus contains WD repeats proposed to mediate protein-protein interactions. Protein purification from HeLa cytosol, cDNA cloning, sequence analysis, cell-free caspase activation assay Cell High 9267021
1998 Apaf-1 binds and hydrolyzes ATP or dATP to ADP/dADP; hydrolysis of ATP/dATP and cytochrome c binding promote Apaf-1 oligomerization into a large multimeric complex that recruits and activates procaspase-9 in a stoichiometric ~1:1 ratio. Once activated, caspase-9 dissociates and cleaves downstream caspases including caspase-3. In vitro reconstitution with purified cytochrome c, recombinant APAF-1 and recombinant procaspase-9; gel filtration chromatography; ATPase assay The Journal of biological chemistry High 10206961
1998 Deletion of the WD-40 repeats from Apaf-1 makes it constitutively active, capable of processing procaspase-9 independent of cytochrome c and dATP. Procaspase-9 is cleaved at Asp-315 by an intrinsic autocatalytic activity of procaspase-9 itself, facilitated by Apaf-1 oligomerization of procaspase-9 molecules. In vitro Apaf-1/procaspase-9 activation system with recombinant components; deletion mutagenesis Molecular cell High 9651578
1998 Apaf-1 requires dATP/ATP hydrolysis (via P-loop) to interact with cytochrome c, self-associate, and bind procaspase-9. A P-loop mutant (K160R) cannot associate with Apaf-1 or bind procaspase-9. The WD-40 repeat region interacts intramolecularly with the N-terminal CED-4 homologous region and negatively regulates Apaf-1 self-association and procaspase-9 activation. The WD-40 repeats are also required for procaspase-3 recruitment. Mutagenesis of Apaf-1 constructs; immunoprecipitation; cell-free caspase activation assay The Journal of biological chemistry High 10393175 9837928
1998 Bcl-XL physically interacts with Apaf-1 (via both the CED-4-like domain and WD-40 repeats) and with caspase-9, forming a ternary complex. Bcl-XL inhibits Apaf-1-dependent processing of caspase-9; it fails to inhibit a constitutively active WD-40-deleted Apaf-1, demonstrating that Bcl-XL acts specifically through Apaf-1. Co-immunoprecipitation in mammalian cells; in vitro inhibition assay with recombinant proteins; mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 9488720 9539746
1998 Apaf-1 is required in vivo for mitochondrial pathway apoptosis and normal brain development. Apaf1-/- mice show reduced apoptosis in the brain, craniofacial abnormalities, and neuronal hyperproliferation. Processing of caspases 2, 3, and 8 is impaired in Apaf1-/- cells. However, Fas-mediated apoptosis in thymocytes is independent of Apaf1. Gene targeting in mice; genetic knockout; caspase activation assays Cell High 9753320 9753321
1999 Caspase-9 in complex with APAF-1 functions as a holoenzyme where caspase-9 is the catalytic subunit and APAF-1 acts as its allosteric regulator, increasing caspase-9 proteolytic activity by several orders of magnitude compared with free enzyme. Enzymatic activity assay comparing free vs. APAF-1-bound caspase-9; cell-free system Genes & development High 10617566
2000 Hsp70 binds directly to Apaf-1 (but not to procaspase-9) via its CARD domain and prevents procaspase-9 recruitment to the apoptosome. Hsp70 allows Apaf-1 oligomer formation but blocks assembly of a functional apoptosome. This was demonstrated independently by two labs. Cell-free apoptosis system; co-immunoprecipitation; binding assays Nature cell biology High 10934466 10934467
2001 Caspase-9 recruits caspase-3 to the Apaf-1 apoptosome via an interaction between the active-site cysteine C287 of caspase-9 and the critical aspartate D175 (cleavage site) of caspase-3. XIAP associates with oligomerized Apaf-1 and/or processed caspase-9, inhibits caspase-3 activation within the apoptosome, and sequesters active caspase-3 within the complex. Cell-free system using cytochrome c/dATP-activated lysates; mutational analysis; biochemical fractionation The EMBO journal High 11230124
2001 Apaf-1 is a direct transcriptional target of E2F1 (which binds to the Apaf-1 promoter) and of p53 (via a p53-responsive element upstream of the APAF-1 transcription start site), linking pRB pathway deregulation and DNA damage signaling to apoptosis. Reporter assays, chromatin immunoprecipitation, cDNA microarray with isogenic cell lines, promoter binding assays Nature cell biology High 11389439 11559530
2000 Aven, a novel apoptosis inhibitor, binds to both Bcl-xL and Apaf-1 (identified by yeast two-hybrid), interferes with Apaf-1 self-association, inhibits caspase proteolytic activation in cell-free extract, and suppresses apoptosis induced by Apaf-1 plus caspase-9. Yeast two-hybrid screen; cell-free caspase activation assay; co-immunoprecipitation Molecular cell Medium 10949025
2000 A novel protein NAC (with NB domain and CARD) interacts selectively with the CARD domain of Apaf-1; NAC association with Apaf-1 is cytochrome c-inducible, forming a mega-complex (>1 MDa). Overexpression of NAC enhances cytochrome c-mediated caspase activation and apoptosis; antisense/DNAzyme knockdown inhibits it. Co-immunoprecipitation; overexpression and antisense knockdown; cell-free caspase activation assay The Journal of biological chemistry Medium 11113115
1999 Boo (an anti-apoptotic Bcl-2 family member) interacts with Apaf-1 at three distinct regions and forms a multimeric complex with Apaf-1 and caspase-9; pro-apoptotic Bak and Bik disrupt the Boo–Apaf-1 association. Co-immunoprecipitation; yeast two-hybrid; pull-down assays The EMBO journal Medium 9878060
1998 Diva (a Bcl-2 family member) directly interacts with Apaf-1 in a BH3-independent manner, preventing Bcl-XL from binding to Apaf-1, as determined by co-immunoprecipitation. Co-immunoprecipitation; mutagenesis of BH3 domain The Journal of biological chemistry Medium 9829980
2001 During apoptosis, caspase-3 (but not caspase-6 or -8) cleaves Apaf-1 into an 84-kDa fragment by removing the CARD H1 helix. An additional cleavage within the WD-40 repeats enables p84 oligomerization (~440 kDa) even without cytochrome c, but the resulting p84 multimer lacks caspase-activating activity due to partial loss of the CARD. Cell-free apoptosis system; incubation with purified caspases; mass spectrometry; gel filtration The Journal of biological chemistry High 11387322
2004 Native Apaf-1 apoptosomes contain Apaf-1, caspase-9, caspase-3, and XIAP as major constituents; cytochrome c is not stably associated with the active complex. Smac/DIABLO and PHAPI enhance native apoptosome catalytic activity by distinct mechanisms; PHAPI also enhances purified caspase-3 activity directly. One-step immunopurification of native apoptosomes; mass spectrometry; in vitro activity assays The EMBO journal High 15103327
2007 Apaf-1 has a non-apoptotic role in DNA damage-induced cell-cycle arrest. Knockdown/knockout of Apaf-1 reduced activation of checkpoint kinase Chk1 after ionizing radiation or chemotherapy. DNA damage induces nuclear translocation of Apaf-1 in vitro; knockdown of Chk1 abrogated Apaf-1-mediated cell-cycle arrest. This function is conserved in C. elegans ced-4. siRNA knockdown in human cells; Apaf-1 knockout mouse cells; ced-4 loss-of-function in C. elegans; kinase activation assays; cell-cycle analysis Molecular cell High 18042457
2015 DNA damage-induced nuclear translocation of Apaf-1 is mediated by nucleoporin Nup107. Apaf-1 associates with Nup107; the CED-4 domain of Apaf-1 directly binds the central domain of Nup107 in an ATR-regulated, phosphorylation-dependent manner. Expression of the Apaf-1-interacting domain of Nup107 blocked nuclear import and reduced Chk1 activation and cell-cycle arrest. Co-immunoprecipitation; domain mapping; dominant-negative interference; Chk1 activation assay; nuclear translocation assay Cell cycle Medium 25695197
2011 Apaf-1 plays a non-apoptotic role in centrosome maturation. Apaf-1 depletion causes centrosome defects impairing microtubule nucleation, cytoskeleton organization, mitotic spindle formation, cell migration, and mitochondrial network regulation. Apaf-1 acts by regulating recruitment of HCA66 (with which it physically interacts) to the centrosome. siRNA knockdown; live cell imaging; immunofluorescence; co-immunoprecipitation; functional assays for migration and spindle formation Journal of cell science Medium 21984814
2015 Cryo-EM structure of intact mammalian apoptosome at 3.8 Å resolution revealed that cytochrome c releases autoinhibition of Apaf-1 through specific interactions with WD40 repeats, and dATP binding triggers conformational changes leading to heptameric apoptosome formation. Structure-guided mutagenesis confirmed the molecular mechanism. Single-particle cryo-EM; structure determination at 3.8 Å; structure-guided biochemical mutagenesis Genes & development High 26543158
2013 Comparison of Apaf-1 crystal structure (monomer) and 9.5 Å EM map of the apoptosome revealed: cytochrome c binds regulatory β-propellers via induced-fit mechanism dependent on shape and charge complementarity; nucleotide exchange causes large rotation of the nucleotide binding module; the N-terminal CARD is not shielded by β-propellers in the inactive monomer. The assembled holo-apoptosome has an acentric CARD-CARD disk with tethered procaspase-9 catalytic domains. Crystal structure of full-length Apaf-1; single-particle EM at ~9.5 Å; comparative structural modeling Biochemistry High 23521171
2002 ER stress-induced apoptosis proceeds via an Apaf-1- and cytochrome c-independent intrinsic pathway. Apaf-1-/- fibroblasts were resistant to tamoxifen but susceptible to thapsigargin and brefeldin-A. The pathway requires caspase-12 and caspase-9 but not caspase-8; immunodepletion of caspase-12 from microsomal fractions blocked caspase activation. Apaf-1-null fibroblasts; cell-free ER stress system; immunodepletion; caspase activity assays The Journal of biological chemistry Medium 11919205
2004 APIP (Apaf-1-interacting protein) binds to the CARD of Apaf-1 in competition with caspase-9, inhibits cytochrome c-induced caspase-3 and caspase-9 activation, and suppresses mitochondrial apoptosis. APIP expression is induced by ischemia/hypoxia, and its forced expression suppresses ischemia-induced skeletal muscle cell death. Co-immunoprecipitation; competitive binding assay; caspase activity assay; siRNA knockdown; overexpression in ischemia/hypoxia model The Journal of biological chemistry Medium 15262985
2005 Protein kinase A (PKA), activated by cAMP, phosphorylates human caspase-9 at serines 99, 183, and 195 but inhibits apoptosome formation by blocking cytochrome c-dependent recruitment of procaspase-9 to Apaf-1 (not by direct phosphorylation of caspase-9 at these sites, as mutagenesis showed those sites are not required). PKA does not inhibit a constitutively active form of Apaf-1. Cell-free apoptosis assay in Xenopus egg extracts and human cell-free system; kinase assay; site-directed mutagenesis; procaspase-9 recruitment assay The Journal of biological chemistry High 15703181
2012 Rsk (90-kDa ribosomal S6 kinase) phosphorylates Apaf-1 at Ser268, enabling binding of 14-3-3ε to phosphorylated Apaf-1, which impedes cytochrome c-driven apoptosome nucleation and downstream caspase activation. High Rsk levels in PC3 prostate cancer cells promote 14-3-3ε binding to Apaf-1 and resistance to cytochrome c. In vitro kinase assay; mutagenesis; co-immunoprecipitation; cell-free apoptosis assay; overexpression in multiple cell lines The EMBO journal High 22246185
2004 Nucling is recruited to the Apaf-1/procaspase-9 complex after UV irradiation and promotes nuclear translocation of this complex; Nucling-deficient cells show downregulated Apaf-1 and cytochrome c expression under stress and are resistant to apoptosis. Co-immunoprecipitation; subcellular fractionation; Nucling knockout cells; UV apoptosis assay The Journal of biological chemistry Medium 15271982
2002 Apaf-1 and cytochrome c undergo nuclear redistribution during stress-induced apoptosis, with perinuclear cytochrome c aggregation preceding nuclear translocation of both cofactors, coinciding with caspase-9-induced nuclear disassembly. Immunofluorescence microscopy; subcellular fractionation during apoptosis FEBS letters Low 12062423
2008 HDAC2 directly regulates APAF1 transcription: HDAC2 protein localizes to the APAF1 promoter (ChIP), HDAC2 siRNA knockdown upregulates APAF1, and HDAC inhibitor-induced apoptosis requires functional HDAC2 to induce APAF1. Stable knockdown of APAF1 reduces apoptotic response to HDAC inhibitors. Chromatin immunoprecipitation (ChIP); siRNA knockdown; stable APAF1 knockdown; apoptosis assays Gastroenterology Medium 18834886
2007 As neurons mature, Apaf-1 expression is completely lost, rendering them insensitive to cytochrome c-mediated apoptosis. After DNA damage, E2F1 restores Apaf-1 expression in mature neurons only when combined with chromatin derepression; in developing neurons E2F1 alone is sufficient. The Apaf-1 promoter associates with active chromatin in developing neurons and repressed chromatin in mature neurons. Primary neuron culture; western blot; chromatin immunoprecipitation; E2F1 overexpression; HDAC inhibitor treatment; cytochrome c microinjection The Journal of cell biology Medium 18056406
2000 The 5' UTR of Apaf-1 mRNA contains an internal ribosome entry segment (IRES) located in a 233-nucleotide region near the 3' end of the 5'UTR; translation of Apaf-1 mRNA initiates exclusively by internal ribosome entry, not cap-dependent translation. Bicistronic reporter assays in multiple human cell lines; deletion mapping of IRES Oncogene Medium 10702798
2019 EV71 3C protease cleaves hnRNP A1, abolishing its binding to the apaf-1 IRES, thereby relieving translational repression of apaf-1 mRNA and allowing IRES-dependent Apaf-1 synthesis, caspase-3 activation, and apoptosis for viral particle release. Viral infection; ectopic 3C protease expression; IRES reporter assay; co-immunoprecipitation of hnRNP A1 with apaf-1 IRES; caspase activation assay PloS one Medium 31498791
2020 Mitochondrial permeability transition (MPT) triggers assembly of an 'Apaf-1 pyroptosome' composed of Apaf-1 and caspase-4 in a 7:2 stoichiometry. Unlike LPS-activated caspase-4 (which directly cleaves GSDMD), caspase-4 in this complex cleaves caspase-3, which then cleaves GSDME to execute pyroptosis. Co-immunoprecipitation; stoichiometry analysis; caspase activation assays; genetic knockouts; biochemical fractionation Cell metabolism Medium 33308446
2003 Primary postnatal cardiomyocytes lack Apaf-1 expression and are consequently resistant to cytochrome c-driven apoptosis despite cytochrome c release. Forced expression of Apaf-1 restores apoptotic competence, and this effect is prevented by Bcl-XL overexpression. Primary cardiomyocyte culture; western blot; forced Apaf-1 expression; cytochrome c release assay; apoptosis assay Cell death and differentiation Medium 12934072

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 2646 9267021
1999 An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. The Journal of biological chemistry 1688 10206961
2000 Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nature cell biology 1259 10934466
2000 Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. The Journal of biological chemistry 1124 11087742
1998 Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Molecular cell 954 9651578
1998 Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 944 9753321
2001 Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 796 11196646
1998 Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 766 9753320
2000 Negative regulation of the Apaf-1 apoptosome by Hsp70. Nature cell biology 691 10934467
1999 Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. The Journal of biological chemistry 622 10329646
2001 Apaf-1 is a transcriptional target for E2F and p53. Nature cell biology 500 11389439
1998 Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proceedings of the National Academy of Sciences of the United States of America 479 9539746
1998 Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. The Journal of biological chemistry 449 9488720
1999 Caspase-9 and APAF-1 form an active holoenzyme. Genes & development 432 10617566
2002 Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. The Journal of biological chemistry 413 11919205
1999 Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. The EMBO journal 387 10393175
2001 Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. The Journal of biological chemistry 380 11390368
2002 The Apaf-1 apoptosome: a large caspase-activating complex. Biochimie 352 12022951
2002 PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. The Journal of biological chemistry 317 12019269
2001 Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes. The EMBO journal 317 11230124
1999 Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway. Nature cell biology 289 10559939
2017 Apaf-1: Regulation and function in cell death. Biochimie 241 28192157
2002 PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B. The Journal of biological chemistry 224 11786556
1998 WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation. The Journal of biological chemistry 213 9837928
2004 Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes. The EMBO journal 206 15103327
2015 Atomic structure of the apoptosome: mechanism of cytochrome c- and dATP-mediated activation of Apaf-1. Genes & development 201 26543158
2000 Adult Apaf-1-deficient mice exhibit male infertility. Developmental biology 178 10656767
2000 Initiation of Apaf-1 translation by internal ribosome entry. Oncogene 176 10702798
1999 HAC-1, a Drosophila homolog of APAF-1 and CED-4 functions in developmental and radiation-induced apoptosis. Molecular cell 173 10619022
2000 The role of Apaf-1, caspase-9, and bid proteins in etoposide- or paclitaxel-induced mitochondrial events during apoptosis. Cancer research 160 10749135
2001 APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis. Cancer research 152 11559530
2004 Apaf-1 and caspase-9 accelerate apoptosis, but do not determine whether factor-deprived or drug-treated cells die. The Journal of cell biology 149 15210730
2014 MicroRNA-23a/b and microRNA-27a/b suppress Apaf-1 protein and alleviate hypoxia-induced neuronal apoptosis. Cell death & disease 148 24651435
2000 Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1. Molecular cell 148 10949025
2020 Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition. Cell metabolism 147 33308446
2000 A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. The Journal of biological chemistry 147 11113115
1998 Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death. The Journal of biological chemistry 144 9829980
1999 Boo, a novel negative regulator of cell death, interacts with Apaf-1. The EMBO journal 143 9878060
2001 An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 134 11535810
2000 Apoptotic protease activating factor 1 (Apaf-1)-independent cell death suppression by Bcl-2. The Journal of experimental medicine 132 10811864
2005 PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1beta secretion. The Journal of biological chemistry 125 15817483
2002 Apaf-1 is a mediator of E2F-1-induced apoptosis. The Journal of biological chemistry 123 12149244
2001 Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells. Blood 121 11435311
2007 Role of APAF-1, E-cadherin and peritumoral lymphocytic infiltration in tumour budding in colorectal cancer. The Journal of pathology 119 17516584
2004 PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase-1. International immunology 116 15096476
1999 Apaf1 and the apoptotic machinery. Cell death and differentiation 101 10578178
2019 Circular RNA Cdr1as sensitizes bladder cancer to cisplatin by upregulating APAF1 expression through miR-1270 inhibition. Molecular oncology 98 31131537
2001 Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Biochemical and biophysical research communications 98 11374873
2007 Nonapoptotic role for Apaf-1 in the DNA damage checkpoint. Molecular cell 94 18042457
2011 Erythropoietin and Wnt1 govern pathways of mTOR, Apaf-1, and XIAP in inflammatory microglia. Current neurovascular research 85 22023617
2005 Protein kinase A regulates caspase-9 activation by Apaf-1 downstream of cytochrome c. The Journal of biological chemistry 78 15703181
2022 APAF1-Binding Long Noncoding RNA Promotes Tumor Growth and Multidrug Resistance in Gastric Cancer by Blocking Apoptosome Assembly. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 76 35975461
2005 Methylation silencing of the Apaf-1 gene in acute leukemia. Molecular cancer research : MCR 69 15972851
2006 Scoring of p53, VEGF, Bcl-2 and APAF-1 immunohistochemistry and interobserver reliability in colorectal cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 68 16741523
2001 Apaf-1 deficiency and neural tube closure defects are found in fog mice. Proceedings of the National Academy of Sciences of the United States of America 68 11504943
2003 Chemical-induced apoptosis: formation of the Apaf-1 apoptosome. Drug metabolism reviews 67 14705865
2001 The adapter protein apoptotic protease-activating factor-1 (Apaf-1) is proteolytically processed during apoptosis. The Journal of biological chemistry 67 11387322
2019 LncRNA MEG3 inhibits cell proliferation and induces apoptosis in laryngeal cancer via miR-23a/APAF-1 axis. Journal of cellular and molecular medicine 63 31328388
2016 DRP1-dependent apoptotic mitochondrial fission occurs independently of BAX, BAK and APAF1 to amplify cell death by BID and oxidative stress. Biochimica et biophysica acta 63 26997499
2011 Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis. Cell cycle (Georgetown, Tex.) 63 22101335
2003 Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes. Cell death and differentiation 61 12934072
2014 Akt1 regulates vascular smooth muscle cell apoptosis through FoxO3a and Apaf1 and protects against arterial remodeling and atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 60 25234814
2004 Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein. The Journal of biological chemistry 59 15262985
2006 Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1 dependent. Oncogene 58 16288204
2009 Apaf-1-independent programmed cell death in mouse development. Cell death and differentiation 57 19960021
2019 miR-187-5p/apaf-1 axis was involved in oxidative stress-mediated apoptosis caused by ammonia via mitochondrial pathway in chicken livers. Toxicology and applied pharmacology 53 31863799
2017 Silica nanoparticles induced intrinsic apoptosis in neuroblastoma SH-SY5Y cells via CytC/Apaf-1 pathway. Environmental toxicology and pharmacology 51 28426994
2013 Changes in Apaf-1 conformation that drive apoptosome assembly. Biochemistry 50 23521171
2012 Oridonin induces apoptosis in gastric cancer through Apaf-1, cytochrome c and caspase-3 signaling pathway. World journal of gastroenterology 50 23326121
2004 Analysis of APAF-1 expression in human cutaneous melanoma progression. Experimental dermatology 49 15009102
2001 Apaf-1 overexpression partially overcomes apoptotic resistance in a cisplatin-selected HeLa cell line. FEBS letters 48 11566177
2004 Nucling recruits Apaf-1/pro-caspase-9 complex for the induction of stress-induced apoptosis. The Journal of biological chemistry 47 15271982
2005 Role of Apaf-1, a key regulator of apoptosis, in melanoma progression and chemoresistance. Experimental dermatology 46 16232302
2003 Physiological and pathological roles of Apaf1 and the apoptosome. Journal of cellular and molecular medicine 46 12767258
2004 Reduced Apaf-1 expression in human cutaneous melanomas. British journal of cancer 44 15305193
2008 An inactivating mutation in HDAC2 leads to dysregulation of apoptosis mediated by APAF1. Gastroenterology 43 18834886
2004 Coupling of caspase-9 to Apaf1 in response to loss of pRb or cytotoxic drugs is cell-type-specific. The EMBO journal 43 14713951
2004 Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth. Development (Cambridge, England) 43 15105372
2011 Apaf1 plays a pro-survival role by regulating centrosome morphology and function. Journal of cell science 42 21984814
2003 Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma. Brain pathology (Zurich, Switzerland) 42 14655749
2020 Mechanism of Heshouwuyin inhibiting the Cyt c/Apaf-1/Caspase-9/Caspase-3 pathway in spermatogenic cell apoptosis. BMC complementary medicine and therapies 40 32527252
2012 Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis. The EMBO journal 40 22246185
2019 EV71 3C protease induces apoptosis by cleavage of hnRNP A1 to promote apaf-1 translation. PloS one 39 31498791
2007 Chromatin modification of Apaf-1 restricts the apoptotic pathway in mature neurons. The Journal of cell biology 39 18056406
2001 Apaf1 in developmental apoptosis and cancer: how many ways to die? Cellular and molecular life sciences : CMLS 39 11706994
2003 Expression and activity of Apaf1 and caspase-9 in granulosa cells during follicular atresia in pig ovaries. Reproduction (Cambridge, England) 38 12814353
2015 Oncogenic miR-23a in Pancreatic Ductal Adenocarcinogenesis Via Inhibiting APAF1. Digestive diseases and sciences 37 25701323
2015 Apaf1 inhibition promotes cell recovery from apoptosis. Protein & cell 33 26361785
2005 Decreased expression of Apaf-1 with progression of melanoma. Pigment cell research 33 15649154
2008 ced-4 and proto-oncogene tfg-1 antagonistically regulate cell size and apoptosis in C. elegans. Current biology : CB 32 18635357
2002 Nuclear Apaf-1 and cytochrome c redistribution following stress-induced apoptosis. FEBS letters 32 12062423
2003 Apoptosome-independent pathway for apoptosis. Biochemical analysis of APAF-1 defects and biological outcomes. The Journal of biological chemistry 31 12773531
2014 The involvement of miR-23a/APAF1 regulation axis in colorectal cancer. International journal of molecular sciences 30 24992592
2007 Epigenetic dysregulation of the death-associated protein kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in multiple myeloma. Journal of clinical pathology 29 17557868
2007 Reduced expression of Apaf-1 in colorectal adenocarcinoma correlates with tumor progression and aggressive phenotype. Annals of surgical oncology 29 17882496
2006 Histone deacetylase activity regulates apaf-1 and caspase 3 expression in the developing mouse retina. Investigative ophthalmology & visual science 29 16799012
2004 Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma. Oncogene 29 15378005
2015 DNA damage-induced nuclear translocation of Apaf-1 is mediated by nucleoporin Nup107. Cell cycle (Georgetown, Tex.) 26 25695197
2005 APAF-1 signaling in human melanoma. Cancer letters 26 16095810
2002 The regulation of APAF1 expression during development and tumourigenesis. Apoptosis : an international journal on programmed cell death 26 11865201

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