@prefix dcterms: <http://purl.org/dc/terms/> .
@prefix ke-wp: <https://ke-wp-mapping.org/vocab#> .
@prefix mapping: <https://ke-wp-mapping.org/mapping/> .
@prefix xsd: <http://www.w3.org/2001/XMLSchema#> .

mapping:31ef20c0-9dd7-4a6c-96e2-fe226c52f871 a ke-wp:KeyEventReactomeMapping ;
    dcterms:creator "github:marvinm2" ;
    dcterms:date "2026-05-08T20:22:43.423053"^^xsd:dateTime ;
    dcterms:identifier "31ef20c0-9dd7-4a6c-96e2-fe226c52f871" ;
    ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
    ke-wp:confidenceLevel "high" ;
    ke-wp:keyEventId "KE 55" ;
    ke-wp:keyEventName "Increase, Cell injury/death" ;
    ke-wp:pathwayDescription "Activation of tumor necrosis factor receptor 1 (TNFR1) can trigger multiple signal transduction pathways to induce cell survival or cell death (Ward C et al. 1999; Micheau O and Tschopp J 2003; Widera D et al. 2006). While pro-survival signaling is initiated and regulated via the activated TNFR1 receptor complex at the cell membrane, cell death signals are induced upon the release of TRADD:TRAF2:RIP1 complex from the membrane to the cytosol where it forms death-inducing signaling complex (DISC) (Micheau O and Tschopp J 2003; Schneider-Brachert W et al. 2004). Upon apoptotic stimulation procaspase-8 or 10 is recruited into the DISC, and close proximity promotes the dimerization, autocatalytic processing, and activation of the initiator caspase-8 (and/or caspase-10) (Wang J et al. 2001; Boatright KM and Salvesen GS 2003). The initiator caspases then process and activate the downstream effector caspases such as caspase-3 in a proteolytic cascade (Stennicke HR et al. 1998). The effector caspases in turn cleave many diverse substrates, ultimately inducing cell death." ;
    ke-wp:pathwayName "TNFR1-induced proapoptotic signaling" ;
    ke-wp:reactomeId "R-HSA-5357786" ;
    ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
    ke-wp:reactomeReleaseVersion "96" ;
    ke-wp:species "Homo sapiens" ;
    ke-wp:suggestionScore 0.5655 .

mapping:71037286-2bae-4c9d-9b0d-cc536f2a5c0a a ke-wp:KeyEventReactomeMapping ;
    dcterms:creator "github:marvinm2" ;
    dcterms:date "2026-05-18T09:56:15.283980"^^xsd:dateTime ;
    dcterms:identifier "71037286-2bae-4c9d-9b0d-cc536f2a5c0a" ;
    ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
    ke-wp:confidenceLevel "medium" ;
    ke-wp:keyEventId "KE 177" ;
    ke-wp:keyEventName "Increase, Mitochondrial dysfunction" ;
    ke-wp:pathwayDescription "The mitochondrial pyruvate dehydrogenase (PDH) complex catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis. PDH inactivation is crucial for glucose conservation when glucose is scarce, while adequate PDH activity is required to allow both ATP and fatty acid production from glucose. The mechanisms that control human PDH activity include its phosphorylation (inactivation) by pyruvate dehydrogenase kinases (PDK 1-4) and its dephosphorylation (activation, reactivation) by pyruvate dehydrogenase phosphate phosphatases (PDP 1 and 2). Isoform-specific differences in kinetic parameters, regulation, and phosphorylation site specificity of the PDKs introduce variations in the regulation of PDC activity in differing endocrine and metabolic states (Sugden and Holness 2003). Further, PDH is inhibited by SIRT4 and the drug dichloroacetic acid (DCA)." ;
    ke-wp:pathwayName "Regulation of pyruvate dehydrogenase (PDH) complex" ;
    ke-wp:reactomeId "R-HSA-204174" ;
    ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
    ke-wp:reactomeReleaseVersion "96" ;
    ke-wp:species "Homo sapiens" ;
    ke-wp:suggestionScore 0.7912 .

mapping:740dfd23-5797-4423-a8a4-4d5872814f70 a ke-wp:KeyEventReactomeMapping ;
    dcterms:creator "github:marvinm2" ;
    dcterms:date "2026-05-08T20:24:34.033794"^^xsd:dateTime ;
    dcterms:identifier "740dfd23-5797-4423-a8a4-4d5872814f70" ;
    ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
    ke-wp:confidenceLevel "medium" ;
    ke-wp:keyEventId "KE 55" ;
    ke-wp:keyEventName "Increase, Cell injury/death" ;
    ke-wp:pathwayDescription "Caspases, a family of cysteine proteases, execute apoptotic cell death. Caspases exist as inactive zymogens in cells and undergo a cascade of catalytic activation at the onset of apoptosis. Initiation of apoptosis occurs through either a cell-intrinsic or cell-extrinsic pathway. Extrinsic pathway cell death signals originate at the plasma membrane where: An extracellular ligand (e.g., FasL) binds to its cell surface transmembrane “death receptor” (e.g., Fas receptor), inducing oligomerization of the receptor (Trauth et al. 1989; Itoh and Nagata 1993; Danial and Korsmeyer 2004). The \"death receptors\" are specialized cell-surface receptors including Fas/CD95, tumor necrosis factor-alpha (TNF-alpha) receptor 1, and two receptors, DR4 and DR5, that bind to the TNF-alpha related apoptosis-inducing ligand (TRAIL). Ligand binding promotes clustering of proteins that bind to the intracellular domain of the receptor (e.g., FADD, or Fas-associated death domain-containing protein), which then binds to the prodomain of initiator caspases (e.g.caspase-8 or -10) to promote their dimerization and activation. Active caspase-8/-10 can then directly cleave and activate effector caspases, such as caspase-3 or it can cleave Bid, which facilitates mitochondrial cytochrome c release. Unique group of proteins termed dependence receptors (DpRs) transduce positive (often prosurvival or progrowth) signals when engaged by ligand, but emit proapoptotic signals in the absence of ligand (Goldschneider and Mehlen 2010). DpR family includes p75 neurotrophin receptor (p75NTR), deleted in colon cancer (DCC), and UNC5 homologs, among others. cell-surface membrane receptors." ;
    ke-wp:pathwayName "Caspase activation via extrinsic apoptotic signalling pathway" ;
    ke-wp:reactomeId "R-HSA-5357769" ;
    ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
    ke-wp:reactomeReleaseVersion "96" ;
    ke-wp:species "Homo sapiens" ;
    ke-wp:suggestionScore 0.5641 .

mapping:a6bce6c0-8575-434c-8560-6bec2eb78ca8 a ke-wp:KeyEventReactomeMapping ;
    dcterms:creator "github:marvinm2" ;
    dcterms:date "2026-07-18T12:18:27.549953"^^xsd:dateTime ;
    dcterms:identifier "a6bce6c0-8575-434c-8560-6bec2eb78ca8" ;
    ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
    ke-wp:confidenceLevel "medium" ;
    ke-wp:keyEventId "KE 1194" ;
    ke-wp:keyEventName "Increase, DNA damage" ;
    ke-wp:pathwayDescription "Activated ATM phosphorylates a number of proteins involved in the DNA damage checkpoint and DNA repair (Thompson and Schild 2002, Ciccia and Elledge 2010), thereby triggering and coordinating accumulation of DNA DSB repair proteins in nuclear foci known as ionizing radiation-induced foci (IRIF). While IRIFs include chromatin regions kilobases away from the actual DSB site, this Reactome pathway represents simplified foci and events that happen proximal to the DNA DSB ends. In general, proteins localizing to the nuclear foci in response to ATM signaling are cooperatively retained at the DNA DSB site, forming a positive feedback loop and amplifying DNA damage response (Soutoglou and Misteli 2008). Activated ATM phosphorylates the NBN (NBS1) subunit of the MRN complex (MRE11A:RAD50:NBN) (Gatei et al. 2000), as well as the nucleosome histone H2AFX (H2AX) on serine residue S139, producing gamma-H2AFX (gamma-H2AX) containing nucleosomes (Rogakou et al. 1998, Burma et al. 2001). H2AFX is phosphorylated on tyrosine 142 (Y142) under basal conditions (Xiao et al. 2009). After ATM-mediated phosphorylation of H2AFX on S139, tyrosine Y142 has to be dephosphorylated by EYA family phosphatases in order for the DNA repair to proceed and to avoid apoptosis induced by DNA DSBs (Cook et al. 2009). Gamma-H2AFX recruits MDC1 to DNA DSBs (Stucki et al. 2005). After ATM phosphorylates MDC1 (Liu et al. 2012), the MRN complex, gamma-H2AFX nucleosomes, and MDC1 serve as a core of the nuclear focus and a platform for the recruitment of other proteins involved in DNA damage signaling and repair (Lukas et al. 2004, Soutoglou and Misteli 2008). RNF8 ubiquitin ligase binds phosphorylated MDC1 (Kolas et al. 2007) and, in cooperation with HERC2 and RNF168 (Bekker-Jensen et al. 2010, Campbell et al. 2012), ubiquitinates H2AFX (Mailand et al. 2007, Huen et al. 2007, Stewart et al. 2009, Doil et al. 2009) and histone demethylases KDM4A and KDM4B (Mallette et al. 2012). Ubiquitinated gamma-H2AFX recruits UIMC1 (RAP80), promoting the assembly of the BRCA1-A complex at DNA DSBs. The BRCA1-A complex consists of RAP80, FAM175A (Abraxas), BRCA1:BARD1 heterodimer, BRCC3 (BRCC36), BRE (BRCC45) and BABAM1 (MERIT40, NBA1) (Wang et al. 2007, Wang and Elledge 2007) Ubiquitin mediated degradation of KDM4A and KDM4B allows TP53BP1 (53BP1) to associate with histone H4 dimethylated on lysine K21 (H4K20Me2 mark) by WHSC1 at DNA DSB sites (Pei et al. 2011). Once recruited to DNA DSBs, both BRCA1:BARD1 heterodimers and TP53BP1 are phosphorylated by ATM (Cortez et al. 1999, Gatei et al. 2000, Kim et al. 2006, Jowsey et al. 2007), which triggers recruitment and activation of CHEK2 (Chk2, Cds1) (Wang et al. 2002, Wilson and Stern 2008, Melchionna et al. 2000). Depending on the cell cycle stage, BRCA1 and TP53BP1 competitively promote either homology directed repair (HDR) or nonhomologous end joining (NHEJ) of DNA DSBs. HDR through homologous recombination repair (HRR) or single strand annealing (SSA) is promoted by BRCA1 in association with RBBP8 (CtIP), while NHEJ is promoted by TP53BP1 in association with RIF1 (Escribano-Diaz et al. 2013)." ;
    ke-wp:pathwayName "Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks" ;
    ke-wp:reactomeId "R-HSA-5693565" ;
    ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
    ke-wp:reactomeReleaseVersion "96" ;
    ke-wp:species "Homo sapiens" ;
    ke-wp:suggestionScore 0.7887 .

mapping:d9d8ef95-e843-497d-a73a-ef7246e646bb a ke-wp:KeyEventReactomeMapping ;
    dcterms:creator "github:marvinm2" ;
    dcterms:date "2026-07-18T12:18:34.411354"^^xsd:dateTime ;
    dcterms:identifier "d9d8ef95-e843-497d-a73a-ef7246e646bb" ;
    ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
    ke-wp:confidenceLevel "high" ;
    ke-wp:keyEventId "KE 1392" ;
    ke-wp:keyEventName "Oxidative Stress" ;
    ke-wp:pathwayDescription "Subpathway representing cytoprotective genes regulated by NFE2L2 (NRF2). NFE2L2 is well-studied for its role in oxidative stress where it gets activated by ROS and then induces a plethora of gene expression regulation the oxidative damage. It induces genes/enzymes that regulate the phase 2 detoxification system (eg. GSTs and Glutathione system), ROS scavenging (SODs,PRDX1 ) and cytoprotection (HO1) by regulating inflammation and tissue damage (Tonelli et al, 2018; Shaw et al, 2020)" ;
    ke-wp:pathwayName "NFE2L2 regulating anti-oxidant/detoxification enzymes" ;
    ke-wp:reactomeId "R-HSA-9818027" ;
    ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
    ke-wp:reactomeReleaseVersion "96" ;
    ke-wp:species "Homo sapiens" ;
    ke-wp:suggestionScore 0.85 .

mapping:fc84d976-c9bd-499e-9d9e-75a027446cb9 a ke-wp:KeyEventReactomeMapping ;
    dcterms:creator "github:marvinm2" ;
    dcterms:date "2026-07-18T12:18:31.084633"^^xsd:dateTime ;
    dcterms:identifier "fc84d976-c9bd-499e-9d9e-75a027446cb9" ;
    ke-wp:aopWikiSnapshotDate "2026-05-06"^^xsd:date ;
    ke-wp:confidenceLevel "medium" ;
    ke-wp:keyEventId "KE 1825" ;
    ke-wp:keyEventName "Increase, Cell death" ;
    ke-wp:pathwayDescription "The tumor suppressor TP53 (p53) exerts its tumor suppressive role in part by regulating transcription of a number of genes involved in cell death, mainly apoptotic cell death. The majority of apoptotic genes that are transcriptional targets of TP53 promote apoptosis, but there are also several TP53 target genes that inhibit apoptosis, providing cells with an opportunity to attempt to repair the damage and/or recover from stress. Pro-apoptotic transcriptional targets of TP53 involve TRAIL death receptors TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2), as well as the FASL/CD95L death receptor FAS (CD95). TRAIL receptors and FAS induce pro-apoptotic signaling in response to external stimuli via extrinsic apoptosis pathway (Wu et al. 1997, Takimoto et al. 2000, Guan et al. 2001, Liu et al. 2004, Ruiz de Almodovar et al. 2004, Liu et al. 2005, Schilling et al. 2009, Wilson et al. 2013). IGFBP3 is a transcriptional target of TP53 that may serve as a ligand for a novel death receptor TMEM219 (Buckbinder et al. 1995, Ingermann et al. 2010). TP53 regulates expression of a number of genes involved in the intrinsic apoptosis pathway, triggered by the cellular stress. Some of TP53 targets, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1, regulate the permeability of the mitochondrial membrane and/or cytochrome C release (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013). Other pro-apoptotic genes, either involved in the intrinsic apoptosis pathway, extrinsic apoptosis pathway or pyroptosis (inflammation-related cell death), which are transcriptionally regulated by TP53 are cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10 (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007). It is uncertain how exactly some of the pro-apoptotic TP53 targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP contribute to apoptosis (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012). TP53 is stabilized in response to cellular stress by phosphorylation on at least serine residues S15 and S20. Since TP53 stabilization precedes the activation of cell death genes, the TP53 tetramer phosphorylated at S15 and S20 is shown as a regulator of pro-apoptotic/pro-cell death genes. Some pro-apoptotic TP53 target genes, such as TP53AIP1, require additional phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). Additional post-translational modifications of TP53 may be involved in transcriptional regulation of genes presented in this pathway and this information will be included as evidence becomes available. Activation of some pro-apoptotic TP53 targets, such as BAX, FAS, BBC3 (PUMA) and TP53I3 (PIG3) requires the presence of the complex of TP53 and an ASPP protein, either PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Samuels-Lev et al. 2001, Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013), indicating how the interaction with specific co-factors modulates the cellular response/outcome. TP53 family members TP63 and or TP73 can also activate some of the pro-apoptotic TP53 targets, such as FAS, BAX, BBC3 (PUMA), TP53I3 (PIG3), CASP1 and PERP (Bergamaschi et al. 2004, Jain et al. 2005, Ihrie et al. 2005, Patel et al. 2008, Schilling et al. 2009, Celardo et al. 2013). For a review of the role of TP53 in apoptosis and pro-apoptotic transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015." ;
    ke-wp:pathwayName "TP53 Regulates Transcription of Cell Death Genes" ;
    ke-wp:reactomeId "R-HSA-5633008" ;
    ke-wp:reactomeReleaseDate "2026-03-25"^^xsd:date ;
    ke-wp:reactomeReleaseVersion "96" ;
    ke-wp:species "Homo sapiens" ;
    ke-wp:suggestionScore 0.7706 .