{"gene":"ING5","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2003,"finding":"ING5 (p28ING5) physically interacts with p300 (a histone acetyltransferase) and p53 in vivo, enhances p53 acetylation at Lys-382, activates the p21/WAF1 promoter, and induces p53-dependent apoptosis and cell cycle arrest.","method":"Co-immunoprecipitation (in vivo), colony formation assay, cell cycle analysis, luciferase reporter assay, western blot","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus multiple functional readouts (promoter activation, acetylation, cell cycle, apoptosis) in a single study, foundational paper replicated by subsequent work","pmids":["12750254"],"is_preprint":false},{"year":2013,"finding":"ING5 acts as a cofactor of Tip60 (KAT5) acetyltransferase to promote acetylation of p53 at K120 in response to DNA damage; ING5 forms a trimeric complex with p53 and Tip60, and K120-acetylated p53 binds the BAX and GADD45 promoters to drive apoptosis. ING5 had no effect on p53 acetylation at K373/382 and did not assist hMOF in acetylating p53-K120.","method":"Co-immunoprecipitation, western blot, chromatin immunoprecipitation (ChIP), site-directed mutagenesis (K120R), siRNA knockdown, gene expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, mutagenesis and functional rescue in one study; independently consistent with foundational interaction data","pmids":["23576563"],"is_preprint":false},{"year":2011,"finding":"ING5 interacts with INCA1 (inhibitor of cyclin A1), and this interaction is required for ING5's antiproliferative and pro-apoptotic functions; ING5 overexpression suppresses cell proliferation, delays S-phase progression, and enhances Fas-induced apoptosis only in INCA1-sufficient cells (Inca1-/- cells are refractory).","method":"Yeast two-hybrid, retroviral overexpression in Inca1+/+ and Inca1-/- MEFs and bone marrow, colony formation assay, cell cycle analysis, apoptosis assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus genetic epistasis in null-allele cells with multiple orthogonal phenotypic readouts in a single rigorous study","pmids":["21750715"],"is_preprint":false},{"year":2015,"finding":"ING5 is phosphorylated at threonine 152 by cyclin E/CDK2 and cyclin A/CDK2 in vitro; this phosphorylation is cell-cycle-regulated in cells and is located in a bipartite nuclear localization sequence, but phosphorylation at T152 alone is not sufficient to alter ING5 subcellular localization. ING5 knockdown reduces tumor cell proliferation and induces apoptosis independently of p53 status.","method":"In vitro kinase assay, phospho-specific antibody, cyclin E/CDK2 overexpression, CDK2 inhibitor (p27KIP1), site-directed mutagenesis, siRNA knockdown, cell cycle analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and cell-based confirmation; single lab but multiple orthogonal methods","pmids":["25860957"],"is_preprint":false},{"year":2017,"finding":"ING5 differentially regulates protein lysine acetylation: overexpression of ING5 promotes autoacetylation of p300 at K1555, K1558, K1560, K1647 and K1794 within/near its HAT domain, activating p300 HAT activity and leading to increased acetylation of p53-K382 and histone H3-K18 and downstream expression of p21 and Bax. A p300 HAT inhibitor (C646) blocked these effects.","method":"SILAC-based quantitative mass spectrometry acetylome profiling, western blot, pharmacological inhibition (C646), gene expression analysis","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative proteomics with site-specific acetylation mapping plus pharmacological inhibitor rescue; single lab with orthogonal validation methods","pmids":["29416718"],"is_preprint":false},{"year":2019,"finding":"ING5 forms homodimers through an N-terminal coiled-coil domain, and can also form heterodimers with ING4. The central region is disordered but binds dsDNA with micromolar affinity. The C-terminal PHD domain binds the H3K4me3 mark equivalently in the dimer. Three cancer-associated N-terminal mutations destabilize the coiled-coil structure and affect cell proliferation and cell cycle distribution.","method":"NMR spectroscopy, X-ray crystallography (coiled-coil domain), size-exclusion chromatography, DNA-binding assay, site-directed mutagenesis, cell cycle analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination (NMR + crystallography) combined with mutagenesis and functional cell-based validation in one rigorous study","pmids":["31026448"],"is_preprint":false},{"year":2017,"finding":"ING5 is the targeting subunit of HBO1, MOZ, and MORF histone acetyltransferase (HAT) complexes and promotes self-renewal of glioblastoma stem-like cells (BTICs) by increasing Oct4, Olig2, and Nestin expression, preventing differentiation, and enhancing PI3K/AKT and MEK/ERK signaling. These effects require the PHD domain of ING5 that binds H3K4me3.","method":"Ectopic expression, PHD-domain mutant analysis, sphere formation assay, immunofluorescence, western blot, in silico TCGA analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mutagenesis plus functional stem-cell assays; single lab, pathway activation measured by western blot without reconstitution","pmids":["28925404"],"is_preprint":false},{"year":2022,"finding":"In a CRISPR/Cas9 synthetic-lethality dropout screen in mouse ESCs, ING5 was identified as a genetic dependency of catalytically dead Set1A/COMPASS; loss of ING5 in Set1A-ΔSET ESCs decreases cell fitness and upregulates differentiation-associated genes, placing ING5 and Set1A/COMPASS as co-regulators of self-renewal vs. differentiation.","method":"CRISPR/Cas9 genome-wide dropout screen, Set1A catalytic-dead knock-in ESCs, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide epistasis screen with genetic validation; single lab, functional readout confirmed by gene expression but no biochemical reconstitution","pmids":["35500115"],"is_preprint":false},{"year":2023,"finding":"In Drosophila, ING5 ortholog Ing5 is a unique binding partner of TCTP; TCTP inhibits nuclear translocation of Ing5 and chromatin binding of the MOZ/MORF (Enok) complex, thereby suppressing H3K23 acetylation. Loss of TCTP rescues Ing5 mutant phenotypes by increasing nuclear Ing5 and Enok chromatin association. Ing5 also controls EGF receptor signaling and organ size via the Yorkie pathway.","method":"Yeast two-hybrid, in vivo Drosophila genetics (loss-of-function mutants), chromatin immunoprecipitation (H3K23ac), immunofluorescence, epistasis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus in vivo genetic epistasis, ChIP for histone mark, and rescue experiments in a non-mammalian ortholog system with multiple orthogonal methods","pmids":["37014852"],"is_preprint":false},{"year":2024,"finding":"ING5 and ING4 are essential components of KAT6A, KAT6B, and KAT7 HAT complexes required for histone H3K14 acetylation and H3K23 acetylation in vivo; Ing4-/-Ing5-/- mouse embryos arrest at E8.5 with global loss of H3K14ac and reduction of H3K23ac, while Ing5-/- mice develop isolated ventricular septal defects and Ing4+/-Ing5-/- hearts show loss of epicardial cells due to defective cell adhesion gene expression.","method":"Knockout mouse generation, western blot (histone marks), immunofluorescence, transcriptome analysis, developmental phenotyping","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic null alleles with direct histone mark quantification and transcriptomic validation; multiple developmental phenotypes tied to specific epigenetic changes","pmids":["38446206"],"is_preprint":false},{"year":2024,"finding":"ING5 overexpression upregulates TIE1 (a tyrosine kinase), which phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) at Y163; pY163-PDK1 causes PDHA1 dephosphorylation and activation, switching metabolism from aerobic glycolysis to oxidative phosphorylation, and suppressing lung cancer cell invasion. PDK1-Y163F mutation abrogates these effects.","method":"Quantitative phosphoproteomics (SILAC), siRNA screening, site-directed mutagenesis (PDK1-Y163F), oxygen consumption/lactate production assays, xenograft mouse model, immunohistochemistry","journal":"Frontiers of medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative phosphoproteomics with mutagenesis, metabolic assays, and in vivo xenograft validation; single lab with multiple orthogonal methods","pmids":["39269568"],"is_preprint":false},{"year":2022,"finding":"ING5 transcription is positively regulated by the transcription factors SRF and YY1 through direct binding to the ING5 promoter (SRF at -717 to -678 bp and YY1 at -48 to +25 bp), forming a SRF-YY1-ING5-p53 complex that activates ING5 expression in gastric cancer cells.","method":"Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), luciferase reporter assay, co-immunoprecipitation","journal":"Frontiers in oncology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — EMSA plus ChIP plus luciferase reporter, three orthogonal methods for the same regulatory interaction; single lab","pmids":["35747809"],"is_preprint":false},{"year":2025,"finding":"ING5 (as part of the MORF acetyltransferase complex with Kat6b and Brpf1) antagonizes transcriptional insulation mediated by the CTCF/cohesin loop-extrusion machinery at developmental genes in mouse ESCs; inhibition of Kat6b partially rescues insulator defects caused by loss of the cohesin loader Nipbl.","method":"Genome-wide CRISPR screen, acute protein depletion (cohesin/CTCF), Hi-C/chromatin topology, transcriptomics, pharmacological inhibition of Kat6b","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen with follow-up chromatin topology and transcriptomics; preprint, single lab, ING5-specific role inferred from complex membership","pmids":["bio_10.1101_2025.02.21.639596"],"is_preprint":true},{"year":2025,"finding":"ING5 knockout mice develop diffuse large B-cell lymphomas at a 6-fold higher rate than wild-type controls, and ING5 KO mouse embryo fibroblasts accumulate in G2, exhibit elevated γH2AX (DNA damage marker), and have abnormal nuclei, establishing an in vivo tumor-suppressor role for ING5 in hematopoietic cells and a function in maintaining genomic integrity.","method":"CRISPR/Cas9 knockout mice, flow cytometry (cell cycle, γH2AX), pathological tumor analysis, wound healing assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with multiple phenotypic readouts including tumor incidence, cell cycle, and DNA damage marker; rigorous controls","pmids":["39787145"],"is_preprint":false},{"year":2017,"finding":"ING5 knockdown in lung cancer A549 cells activates EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways to promote EMT and metastasis; pharmacological inhibition of PI3K (ZSTK474) or STAT3 (Niclosamide) abolishes ING5-knockdown-promoted migration, invasion, and metastasis in mouse xenograft models.","method":"Phospho-kinase array, western blot, shRNA knockdown, pharmacological inhibition, xenograft tail-vein injection metastasis model, EMT marker analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-kinase array plus pharmacological rescue in vivo; single lab, pathway activation inferred from phosphorylation changes","pmids":["28903339"],"is_preprint":false},{"year":2023,"finding":"ING5 overexpression in lung cancer cells induces upregulation of miR-34c-5p, which directly targets the 3'UTR of Snail1 (confirmed by dual-luciferase reporter), reducing Snail1 expression and inactivating the TGF-β/Smad3 pathway to inhibit EMT and invasion.","method":"Overexpression, dual-luciferase reporter assay, miRNA overexpression/inhibition, TGF-β inhibitor (LY2157299), xenograft metastasis model (tail vein injection), TCGA data analysis","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validation of miRNA-target interaction plus pathway rescue with inhibitor; single lab, ING5→miR-34c-5p linkage by overexpression only","pmids":["37249332"],"is_preprint":false},{"year":2010,"finding":"Three missense mutations in ING5 located within the leucine zipper-like (LZL) and novel conserved region (NCR) domains were detected specifically in oral squamous cell carcinoma tumors; five alternative splicing variants of ING5 were also identified. ING5 mRNA was decreased in 61% of primary tumors, implicating these structural domains in tumor-suppressor function.","method":"RT-PCR, sequencing, quantitative real-time RT-PCR (qRT-PCR), analysis of matched normal/tumor pairs","journal":"International journal of cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mutation identification by sequencing in primary tumors without functional reconstitution; no in vitro or biochemical validation of mutant effects","pmids":["20131318"],"is_preprint":false},{"year":2023,"finding":"ING5 is required for normal hematopoietic cell numbers in the fetal liver in a cell-extrinsic manner; Ing5-null mice showed decreased fetal liver cellularity, fewer hematopoietic stem cells, and perturbed erythropoiesis, but competitive transplantation showed no cell-intrinsic long-term repopulation defect.","method":"Knockout mouse model (null allele), cell counting, flow cytometry, competitive bone-marrow transplantation","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic null allele with competitive transplantation distinguishing cell-intrinsic from extrinsic effects; single lab","pmids":["37275850"],"is_preprint":false}],"current_model":"ING5 is an epigenetic reader/adaptor protein that binds the H3K4me3 mark via its PHD domain, targets HBO1, MOZ/MORF, and KAT6/KAT7 histone acetyltransferase complexes to chromatin to promote H3K14 and H3K23 acetylation, and acts as a cofactor for p300 autoacetylation and Tip60-mediated p53-K120 acetylation; it forms homodimers and ING4 heterodimers through an N-terminal coiled-coil domain, is phosphorylated at T152 by CDK2, requires INCA1 for its antiproliferative effects, suppresses tumor progression by restraining EGFR/PI3K/Akt, IL-6/STAT3, and WNT/β-catenin pathways, inhibits aerobic glycolysis through TIE1-mediated PDK1-Y163 phosphorylation, and its transcription is activated by a SRF–YY1–p53 complex at the ING5 promoter."},"narrative":{"mechanistic_narrative":"ING5 is a chromatin-associated reader/adaptor that targets histone acetyltransferase complexes to genes regulating proliferation, self-renewal, and differentiation, and functions broadly as a tumor suppressor [PMID:38446206, PMID:39787145]. It is the targeting subunit of HBO1, MOZ/MORF, and KAT6A/KAT6B/KAT7 acetyltransferase complexes, engaging chromatin through a C-terminal PHD domain that binds the H3K4me3 mark and thereby directing H3K14 and H3K23 acetylation in vivo [PMID:28925404, PMID:38446206]. Loss of ING4/ING5 abolishes global H3K14ac and reduces H3K23ac, causing embryonic arrest, while Ing5 nulls show isolated developmental defects and a 6-fold elevated lymphoma incidence with accumulation of γH2AX-positive cells, linking ING5 to genomic integrity [PMID:38446206, PMID:39787145]. Structurally, ING5 forms homodimers and ING4 heterodimers via an N-terminal coiled-coil, with a disordered central region that binds dsDNA and a PHD domain that reads H3K4me3 in the dimeric state; cancer-associated N-terminal mutations destabilize the coiled-coil and perturb cell cycle progression [PMID:31026448]. Beyond its HAT-targeting role, ING5 functions as a cofactor that enhances p300 autoacetylation to activate its HAT activity and promotes Tip60-mediated acetylation of p53 at K120, driving p53-dependent transcription of p21, BAX, and GADD45 and consequent apoptosis and cell cycle arrest [PMID:12750254, PMID:23576563, PMID:29416718]. ING5 restrains oncogenic signaling—suppressing EGFR/PI3K/Akt and IL-6/STAT3-driven EMT and metastasis—and reprograms metabolism away from aerobic glycolysis through a TIE1→PDK1-Y163→PDHA1 axis [PMID:39269568, PMID:28903339]. Its antiproliferative output requires the partner INCA1 [PMID:21750715], it is phosphorylated at T152 by cyclin/CDK2 within a bipartite nuclear localization sequence [PMID:25860957], and its own transcription is activated by an SRF–YY1–p53 complex at the ING5 promoter [PMID:35747809].","teleology":[{"year":2003,"claim":"Established ING5 as a p53 co-activator, answering whether ING5 functions in the p53 tumor-suppressor axis by linking it to histone acetyltransferase activity.","evidence":"Reciprocal Co-IP, luciferase reporter, cell cycle and apoptosis assays in human cells","pmids":["12750254"],"confidence":"High","gaps":["Did not define which HAT complexes ING5 targets to chromatin","Mechanism of p300 activation by ING5 not resolved"]},{"year":2010,"claim":"Implicated specific ING5 structural domains in tumor suppression by finding cancer-restricted missense mutations and reduced mRNA, framing ING5 as a candidate tumor suppressor.","evidence":"RT-PCR, sequencing and qRT-PCR of matched oral squamous cell carcinoma tumor/normal pairs","pmids":["20131318"],"confidence":"Low","gaps":["Mutations not functionally reconstituted","No biochemical validation of mutant effects on HAT targeting"]},{"year":2011,"claim":"Identified INCA1 as the partner required for ING5's growth-suppressive output, showing the antiproliferative function is not cell-autonomous to ING5 alone.","evidence":"Yeast two-hybrid plus genetic epistasis in Inca1-/- MEFs and bone marrow with phenotypic readouts","pmids":["21750715"],"confidence":"High","gaps":["Molecular mechanism by which INCA1 enables ING5 function unknown","No structural basis for the interaction"]},{"year":2013,"claim":"Defined a DNA-damage-specific role by showing ING5 is a Tip60 cofactor for p53-K120 acetylation, distinguishing it from the earlier p300/K382 pathway and routing p53 toward apoptotic targets.","evidence":"Co-IP, ChIP, K120R mutagenesis and siRNA in human cells","pmids":["23576563"],"confidence":"High","gaps":["How DNA damage triggers trimeric complex assembly not established","Site selectivity vs hMOF mechanistically unexplained"]},{"year":2015,"claim":"Connected ING5 to cell-cycle control by showing CDK2 phosphorylates T152 within its NLS, while also demonstrating p53-independent proliferation effects.","evidence":"In vitro kinase assay, phospho-specific antibody, mutagenesis and siRNA cell-cycle analysis","pmids":["25860957"],"confidence":"High","gaps":["T152 phosphorylation alone does not alter localization—functional consequence unclear","Identity of the p53-independent effector pathway unknown"]},{"year":2017,"claim":"Established ING5 as the targeting subunit of HBO1/MOZ/MORF HAT complexes and its PHD-H3K4me3 reading as required for glioblastoma stem cell self-renewal, defining the chromatin-recruitment mechanism.","evidence":"PHD-domain mutant analysis, sphere formation assays and western blot in BTICs","pmids":["28925404"],"confidence":"Medium","gaps":["Pathway activation measured by western blot without complex reconstitution","Direct chromatin targets in stem cells not mapped"]},{"year":2017,"claim":"Showed ING5 promotes p300 autoacetylation at specific HAT-domain lysines to stimulate its enzymatic activity, providing a biochemical basis for ING5-driven p53/histone acetylation.","evidence":"SILAC acetylome mass spectrometry with site mapping and C646 inhibitor rescue","pmids":["29416718"],"confidence":"High","gaps":["Whether ING5 directly contacts the p300 HAT domain not shown","Stoichiometry of activation unresolved"]},{"year":2017,"claim":"Demonstrated ING5 loss activates EGFR/PI3K/Akt and IL-6/STAT3 signaling to drive EMT and metastasis, establishing ING5 as a restraint on oncogenic signaling.","evidence":"Phospho-kinase array, shRNA, pharmacological rescue and xenograft metastasis model","pmids":["28903339"],"confidence":"Medium","gaps":["Pathway activation inferred from phosphorylation changes only","Link between chromatin function and signaling suppression unclear"]},{"year":2019,"claim":"Resolved ING5 quaternary structure, showing N-terminal coiled-coil-mediated homo/heterodimerization, central dsDNA binding, and PHD reading of H3K4me3, and linking cancer mutations to coiled-coil destabilization.","evidence":"NMR, X-ray crystallography, SEC, DNA-binding assays and mutagenesis with cell cycle analysis","pmids":["31026448"],"confidence":"High","gaps":["Functional role of ING4 heterodimerization vs homodimerization undefined","How dimerization couples to HAT complex assembly unknown"]},{"year":2022,"claim":"Placed ING5 genetically as a co-regulator of self-renewal with Set1A/COMPASS, identifying it as a dependency of catalytically dead COMPASS in ESCs.","evidence":"Genome-wide CRISPR dropout screen in Set1A-ΔSET knock-in ESCs with gene expression","pmids":["35500115"],"confidence":"Medium","gaps":["No biochemical link between ING5 and COMPASS shown","Mechanism of synthetic lethality unresolved"]},{"year":2022,"claim":"Identified the upstream transcriptional control of ING5 itself, showing SRF and YY1 directly activate its promoter as an SRF-YY1-ING5-p53 complex.","evidence":"EMSA, ChIP, luciferase reporter and Co-IP in gastric cancer cells","pmids":["35747809"],"confidence":"High","gaps":["Upstream signals controlling SRF/YY1 occupancy not defined","Functional role of p53 within the promoter complex unclear"]},{"year":2023,"claim":"Used the Drosophila ortholog to show TCTP gates Ing5 nuclear translocation and MOZ/MORF chromatin binding, identifying a regulatory switch on H3K23 acetylation and EGFR/Yorkie signaling.","evidence":"Yeast two-hybrid, in vivo genetics, H3K23ac ChIP and epistasis in Drosophila","pmids":["37014852"],"confidence":"High","gaps":["Conservation of TCTP regulation in mammals not tested","Mechanism of TCTP-mediated nuclear exclusion unknown"]},{"year":2023,"claim":"Defined an ING5→miR-34c-5p→Snail1 axis suppressing TGF-β/Smad3-driven EMT, providing a transcriptional/post-transcriptional route for metastasis suppression.","evidence":"Overexpression, dual-luciferase 3'UTR validation, TGF-β inhibitor and xenograft model","pmids":["37249332"],"confidence":"Medium","gaps":["ING5→miR-34c-5p linkage shown by overexpression only","Direct chromatin mechanism for miR-34c-5p induction not shown"]},{"year":2023,"claim":"Showed ING5 supports fetal liver hematopoiesis cell-extrinsically, refining its tissue-level role apart from intrinsic stem-cell function.","evidence":"Ing5-null mice, flow cytometry and competitive bone-marrow transplantation","pmids":["37275850"],"confidence":"Medium","gaps":["Cell-extrinsic mediator not identified","Niche cell type responsible undefined"]},{"year":2024,"claim":"Established ING4/ING5 as essential, non-redundant components of KAT6A/KAT6B/KAT7 complexes required for H3K14ac and H3K23ac in vivo, tying epigenetic marks to specific developmental phenotypes.","evidence":"Knockout mouse genetics, histone-mark western blot, transcriptomics and developmental phenotyping","pmids":["38446206"],"confidence":"High","gaps":["Gene-specific targeting rules of ING5 within these complexes unclear","Basis of tissue-specific phenotypes (heart) not fully resolved"]},{"year":2024,"claim":"Identified a metabolic tumor-suppressive mechanism: ING5 induces TIE1 to phosphorylate PDK1-Y163, activating PDHA1 and shifting cells from glycolysis to oxidative phosphorylation to suppress invasion.","evidence":"SILAC phosphoproteomics, PDK1-Y163F mutagenesis, metabolic assays and xenografts","pmids":["39269568"],"confidence":"High","gaps":["How ING5 chromatin function induces TIE1 not shown","Generality beyond lung cancer untested"]},{"year":2025,"claim":"Provided in vivo proof of ING5 tumor suppression and genome maintenance, showing knockout mice develop lymphoma and KO MEFs accumulate in G2 with elevated DNA damage.","evidence":"CRISPR knockout mice, tumor pathology and flow cytometry for cell cycle/γH2AX","pmids":["39787145"],"confidence":"High","gaps":["Molecular cause of γH2AX accumulation not defined","Link between HAT-complex function and genome stability unresolved"]},{"year":2025,"claim":"Linked ING5 (via MORF/Kat6b/Brpf1) to chromatin topology, showing it antagonizes CTCF/cohesin-mediated transcriptional insulation at developmental genes.","evidence":"Genome-wide CRISPR screen, acute depletion, Hi-C and Kat6b inhibition in ESCs (preprint)","pmids":["bio_10.1101_2025.02.21.639596"],"confidence":"Medium","gaps":["ING5-specific role inferred from complex membership","Preprint, single lab; direct ING5 contribution to insulation not isolated"]},{"year":null,"claim":"How ING5's PHD/H3K4me3 reading and HAT-complex targeting mechanistically connect to its downstream signaling, metabolic, and genome-stability outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking chromatin function to EGFR/STAT3/Wnt and TIE1-PDK1 axes","Mammalian regulators of ING5 nuclear localization beyond CDK2 unknown","Genomic targets directing ING5/HAT acetylation in each tissue not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[5,6,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9,6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,9,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,14]}],"complexes":["HBO1 HAT complex","MOZ/MORF (KAT6) HAT complex","KAT7 HAT complex"],"partners":["P300","TP53","KAT5","INCA1","ING4","CDK2","TCTP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WYH8","full_name":"Inhibitor of growth protein 5","aliases":["p28ING5"],"length_aa":240,"mass_kda":27.8,"function":"Component of the HBO1 complex, which specifically mediates acetylation of histone H3 at 'Lys-14' (H3K14ac) and, to a lower extent, acetylation of histone H4 (PubMed:24065767). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity (PubMed:16387653). Through chromatin acetylation it may regulate DNA replication and may function as a transcriptional coactivator (PubMed:12750254, PubMed:16387653). Inhibits cell growth, induces a delay in S-phase progression and enhances Fas-induced apoptosis in an INCA1-dependent manner (PubMed:21750715)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8WYH8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ING5","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ING5","total_profiled":1310},"omim":[{"mim_id":"617333","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND PTOSIS; IDDDFP","url":"https://www.omim.org/entry/617333"},{"mim_id":"608525","title":"INHIBITOR OF GROWTH 5; ING5","url":"https://www.omim.org/entry/608525"},{"mim_id":"608524","title":"INHIBITOR OF GROWTH 4; ING4","url":"https://www.omim.org/entry/608524"},{"mim_id":"602410","title":"BROMODOMAIN- AND PHD FINGER-CONTAINING PROTEIN; BRPF1","url":"https://www.omim.org/entry/602410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ING5"},"hgnc":{"alias_symbol":["FLJ23842","p28ING5"],"prev_symbol":[]},"alphafold":{"accession":"Q8WYH8","domains":[{"cath_id":"3.30.40.10","chopping":"198-238","consensus_level":"high","plddt":90.2205,"start":198,"end":238},{"cath_id":"1.10.287","chopping":"1-117","consensus_level":"medium","plddt":91.5621,"start":1,"end":117}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WYH8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WYH8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WYH8-F1-predicted_aligned_error_v6.png","plddt_mean":78.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ING5","jax_strain_url":"https://www.jax.org/strain/search?query=ING5"},"sequence":{"accession":"Q8WYH8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WYH8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WYH8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WYH8"}},"corpus_meta":[{"pmid":"30642385","id":"PMC_30642385","title":"Exosomal 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[\n    {\n      \"year\": 2003,\n      \"finding\": \"ING5 (p28ING5) physically interacts with p300 (a histone acetyltransferase) and p53 in vivo, enhances p53 acetylation at Lys-382, activates the p21/WAF1 promoter, and induces p53-dependent apoptosis and cell cycle arrest.\",\n      \"method\": \"Co-immunoprecipitation (in vivo), colony formation assay, cell cycle analysis, luciferase reporter assay, western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus multiple functional readouts (promoter activation, acetylation, cell cycle, apoptosis) in a single study, foundational paper replicated by subsequent work\",\n      \"pmids\": [\"12750254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ING5 acts as a cofactor of Tip60 (KAT5) acetyltransferase to promote acetylation of p53 at K120 in response to DNA damage; ING5 forms a trimeric complex with p53 and Tip60, and K120-acetylated p53 binds the BAX and GADD45 promoters to drive apoptosis. ING5 had no effect on p53 acetylation at K373/382 and did not assist hMOF in acetylating p53-K120.\",\n      \"method\": \"Co-immunoprecipitation, western blot, chromatin immunoprecipitation (ChIP), site-directed mutagenesis (K120R), siRNA knockdown, gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, mutagenesis and functional rescue in one study; independently consistent with foundational interaction data\",\n      \"pmids\": [\"23576563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ING5 interacts with INCA1 (inhibitor of cyclin A1), and this interaction is required for ING5's antiproliferative and pro-apoptotic functions; ING5 overexpression suppresses cell proliferation, delays S-phase progression, and enhances Fas-induced apoptosis only in INCA1-sufficient cells (Inca1-/- cells are refractory).\",\n      \"method\": \"Yeast two-hybrid, retroviral overexpression in Inca1+/+ and Inca1-/- MEFs and bone marrow, colony formation assay, cell cycle analysis, apoptosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus genetic epistasis in null-allele cells with multiple orthogonal phenotypic readouts in a single rigorous study\",\n      \"pmids\": [\"21750715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ING5 is phosphorylated at threonine 152 by cyclin E/CDK2 and cyclin A/CDK2 in vitro; this phosphorylation is cell-cycle-regulated in cells and is located in a bipartite nuclear localization sequence, but phosphorylation at T152 alone is not sufficient to alter ING5 subcellular localization. ING5 knockdown reduces tumor cell proliferation and induces apoptosis independently of p53 status.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, cyclin E/CDK2 overexpression, CDK2 inhibitor (p27KIP1), site-directed mutagenesis, siRNA knockdown, cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and cell-based confirmation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25860957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ING5 differentially regulates protein lysine acetylation: overexpression of ING5 promotes autoacetylation of p300 at K1555, K1558, K1560, K1647 and K1794 within/near its HAT domain, activating p300 HAT activity and leading to increased acetylation of p53-K382 and histone H3-K18 and downstream expression of p21 and Bax. A p300 HAT inhibitor (C646) blocked these effects.\",\n      \"method\": \"SILAC-based quantitative mass spectrometry acetylome profiling, western blot, pharmacological inhibition (C646), gene expression analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative proteomics with site-specific acetylation mapping plus pharmacological inhibitor rescue; single lab with orthogonal validation methods\",\n      \"pmids\": [\"29416718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ING5 forms homodimers through an N-terminal coiled-coil domain, and can also form heterodimers with ING4. The central region is disordered but binds dsDNA with micromolar affinity. The C-terminal PHD domain binds the H3K4me3 mark equivalently in the dimer. Three cancer-associated N-terminal mutations destabilize the coiled-coil structure and affect cell proliferation and cell cycle distribution.\",\n      \"method\": \"NMR spectroscopy, X-ray crystallography (coiled-coil domain), size-exclusion chromatography, DNA-binding assay, site-directed mutagenesis, cell cycle analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination (NMR + crystallography) combined with mutagenesis and functional cell-based validation in one rigorous study\",\n      \"pmids\": [\"31026448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ING5 is the targeting subunit of HBO1, MOZ, and MORF histone acetyltransferase (HAT) complexes and promotes self-renewal of glioblastoma stem-like cells (BTICs) by increasing Oct4, Olig2, and Nestin expression, preventing differentiation, and enhancing PI3K/AKT and MEK/ERK signaling. These effects require the PHD domain of ING5 that binds H3K4me3.\",\n      \"method\": \"Ectopic expression, PHD-domain mutant analysis, sphere formation assay, immunofluorescence, western blot, in silico TCGA analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mutagenesis plus functional stem-cell assays; single lab, pathway activation measured by western blot without reconstitution\",\n      \"pmids\": [\"28925404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In a CRISPR/Cas9 synthetic-lethality dropout screen in mouse ESCs, ING5 was identified as a genetic dependency of catalytically dead Set1A/COMPASS; loss of ING5 in Set1A-ΔSET ESCs decreases cell fitness and upregulates differentiation-associated genes, placing ING5 and Set1A/COMPASS as co-regulators of self-renewal vs. differentiation.\",\n      \"method\": \"CRISPR/Cas9 genome-wide dropout screen, Set1A catalytic-dead knock-in ESCs, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide epistasis screen with genetic validation; single lab, functional readout confirmed by gene expression but no biochemical reconstitution\",\n      \"pmids\": [\"35500115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Drosophila, ING5 ortholog Ing5 is a unique binding partner of TCTP; TCTP inhibits nuclear translocation of Ing5 and chromatin binding of the MOZ/MORF (Enok) complex, thereby suppressing H3K23 acetylation. Loss of TCTP rescues Ing5 mutant phenotypes by increasing nuclear Ing5 and Enok chromatin association. Ing5 also controls EGF receptor signaling and organ size via the Yorkie pathway.\",\n      \"method\": \"Yeast two-hybrid, in vivo Drosophila genetics (loss-of-function mutants), chromatin immunoprecipitation (H3K23ac), immunofluorescence, epistasis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus in vivo genetic epistasis, ChIP for histone mark, and rescue experiments in a non-mammalian ortholog system with multiple orthogonal methods\",\n      \"pmids\": [\"37014852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ING5 and ING4 are essential components of KAT6A, KAT6B, and KAT7 HAT complexes required for histone H3K14 acetylation and H3K23 acetylation in vivo; Ing4-/-Ing5-/- mouse embryos arrest at E8.5 with global loss of H3K14ac and reduction of H3K23ac, while Ing5-/- mice develop isolated ventricular septal defects and Ing4+/-Ing5-/- hearts show loss of epicardial cells due to defective cell adhesion gene expression.\",\n      \"method\": \"Knockout mouse generation, western blot (histone marks), immunofluorescence, transcriptome analysis, developmental phenotyping\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic null alleles with direct histone mark quantification and transcriptomic validation; multiple developmental phenotypes tied to specific epigenetic changes\",\n      \"pmids\": [\"38446206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ING5 overexpression upregulates TIE1 (a tyrosine kinase), which phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) at Y163; pY163-PDK1 causes PDHA1 dephosphorylation and activation, switching metabolism from aerobic glycolysis to oxidative phosphorylation, and suppressing lung cancer cell invasion. PDK1-Y163F mutation abrogates these effects.\",\n      \"method\": \"Quantitative phosphoproteomics (SILAC), siRNA screening, site-directed mutagenesis (PDK1-Y163F), oxygen consumption/lactate production assays, xenograft mouse model, immunohistochemistry\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative phosphoproteomics with mutagenesis, metabolic assays, and in vivo xenograft validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39269568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ING5 transcription is positively regulated by the transcription factors SRF and YY1 through direct binding to the ING5 promoter (SRF at -717 to -678 bp and YY1 at -48 to +25 bp), forming a SRF-YY1-ING5-p53 complex that activates ING5 expression in gastric cancer cells.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), luciferase reporter assay, co-immunoprecipitation\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EMSA plus ChIP plus luciferase reporter, three orthogonal methods for the same regulatory interaction; single lab\",\n      \"pmids\": [\"35747809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ING5 (as part of the MORF acetyltransferase complex with Kat6b and Brpf1) antagonizes transcriptional insulation mediated by the CTCF/cohesin loop-extrusion machinery at developmental genes in mouse ESCs; inhibition of Kat6b partially rescues insulator defects caused by loss of the cohesin loader Nipbl.\",\n      \"method\": \"Genome-wide CRISPR screen, acute protein depletion (cohesin/CTCF), Hi-C/chromatin topology, transcriptomics, pharmacological inhibition of Kat6b\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen with follow-up chromatin topology and transcriptomics; preprint, single lab, ING5-specific role inferred from complex membership\",\n      \"pmids\": [\"bio_10.1101_2025.02.21.639596\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ING5 knockout mice develop diffuse large B-cell lymphomas at a 6-fold higher rate than wild-type controls, and ING5 KO mouse embryo fibroblasts accumulate in G2, exhibit elevated γH2AX (DNA damage marker), and have abnormal nuclei, establishing an in vivo tumor-suppressor role for ING5 in hematopoietic cells and a function in maintaining genomic integrity.\",\n      \"method\": \"CRISPR/Cas9 knockout mice, flow cytometry (cell cycle, γH2AX), pathological tumor analysis, wound healing assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with multiple phenotypic readouts including tumor incidence, cell cycle, and DNA damage marker; rigorous controls\",\n      \"pmids\": [\"39787145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ING5 knockdown in lung cancer A549 cells activates EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways to promote EMT and metastasis; pharmacological inhibition of PI3K (ZSTK474) or STAT3 (Niclosamide) abolishes ING5-knockdown-promoted migration, invasion, and metastasis in mouse xenograft models.\",\n      \"method\": \"Phospho-kinase array, western blot, shRNA knockdown, pharmacological inhibition, xenograft tail-vein injection metastasis model, EMT marker analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-kinase array plus pharmacological rescue in vivo; single lab, pathway activation inferred from phosphorylation changes\",\n      \"pmids\": [\"28903339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ING5 overexpression in lung cancer cells induces upregulation of miR-34c-5p, which directly targets the 3'UTR of Snail1 (confirmed by dual-luciferase reporter), reducing Snail1 expression and inactivating the TGF-β/Smad3 pathway to inhibit EMT and invasion.\",\n      \"method\": \"Overexpression, dual-luciferase reporter assay, miRNA overexpression/inhibition, TGF-β inhibitor (LY2157299), xenograft metastasis model (tail vein injection), TCGA data analysis\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validation of miRNA-target interaction plus pathway rescue with inhibitor; single lab, ING5→miR-34c-5p linkage by overexpression only\",\n      \"pmids\": [\"37249332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Three missense mutations in ING5 located within the leucine zipper-like (LZL) and novel conserved region (NCR) domains were detected specifically in oral squamous cell carcinoma tumors; five alternative splicing variants of ING5 were also identified. ING5 mRNA was decreased in 61% of primary tumors, implicating these structural domains in tumor-suppressor function.\",\n      \"method\": \"RT-PCR, sequencing, quantitative real-time RT-PCR (qRT-PCR), analysis of matched normal/tumor pairs\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mutation identification by sequencing in primary tumors without functional reconstitution; no in vitro or biochemical validation of mutant effects\",\n      \"pmids\": [\"20131318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ING5 is required for normal hematopoietic cell numbers in the fetal liver in a cell-extrinsic manner; Ing5-null mice showed decreased fetal liver cellularity, fewer hematopoietic stem cells, and perturbed erythropoiesis, but competitive transplantation showed no cell-intrinsic long-term repopulation defect.\",\n      \"method\": \"Knockout mouse model (null allele), cell counting, flow cytometry, competitive bone-marrow transplantation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic null allele with competitive transplantation distinguishing cell-intrinsic from extrinsic effects; single lab\",\n      \"pmids\": [\"37275850\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ING5 is an epigenetic reader/adaptor protein that binds the H3K4me3 mark via its PHD domain, targets HBO1, MOZ/MORF, and KAT6/KAT7 histone acetyltransferase complexes to chromatin to promote H3K14 and H3K23 acetylation, and acts as a cofactor for p300 autoacetylation and Tip60-mediated p53-K120 acetylation; it forms homodimers and ING4 heterodimers through an N-terminal coiled-coil domain, is phosphorylated at T152 by CDK2, requires INCA1 for its antiproliferative effects, suppresses tumor progression by restraining EGFR/PI3K/Akt, IL-6/STAT3, and WNT/β-catenin pathways, inhibits aerobic glycolysis through TIE1-mediated PDK1-Y163 phosphorylation, and its transcription is activated by a SRF–YY1–p53 complex at the ING5 promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ING5 is a chromatin-associated reader/adaptor that targets histone acetyltransferase complexes to genes regulating proliferation, self-renewal, and differentiation, and functions broadly as a tumor suppressor [#9, #13]. It is the targeting subunit of HBO1, MOZ/MORF, and KAT6A/KAT6B/KAT7 acetyltransferase complexes, engaging chromatin through a C-terminal PHD domain that binds the H3K4me3 mark and thereby directing H3K14 and H3K23 acetylation in vivo [#6, #9]. Loss of ING4/ING5 abolishes global H3K14ac and reduces H3K23ac, causing embryonic arrest, while Ing5 nulls show isolated developmental defects and a 6-fold elevated lymphoma incidence with accumulation of γH2AX-positive cells, linking ING5 to genomic integrity [#9, #13]. Structurally, ING5 forms homodimers and ING4 heterodimers via an N-terminal coiled-coil, with a disordered central region that binds dsDNA and a PHD domain that reads H3K4me3 in the dimeric state; cancer-associated N-terminal mutations destabilize the coiled-coil and perturb cell cycle progression [#5]. Beyond its HAT-targeting role, ING5 functions as a cofactor that enhances p300 autoacetylation to activate its HAT activity and promotes Tip60-mediated acetylation of p53 at K120, driving p53-dependent transcription of p21, BAX, and GADD45 and consequent apoptosis and cell cycle arrest [#0, #1, #4]. ING5 restrains oncogenic signaling—suppressing EGFR/PI3K/Akt and IL-6/STAT3-driven EMT and metastasis—and reprograms metabolism away from aerobic glycolysis through a TIE1→PDK1-Y163→PDHA1 axis [#10, #14]. Its antiproliferative output requires the partner INCA1 [#2], it is phosphorylated at T152 by cyclin/CDK2 within a bipartite nuclear localization sequence [#3], and its own transcription is activated by an SRF–YY1–p53 complex at the ING5 promoter [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established ING5 as a p53 co-activator, answering whether ING5 functions in the p53 tumor-suppressor axis by linking it to histone acetyltransferase activity.\",\n      \"evidence\": \"Reciprocal Co-IP, luciferase reporter, cell cycle and apoptosis assays in human cells\",\n      \"pmids\": [\"12750254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which HAT complexes ING5 targets to chromatin\", \"Mechanism of p300 activation by ING5 not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Implicated specific ING5 structural domains in tumor suppression by finding cancer-restricted missense mutations and reduced mRNA, framing ING5 as a candidate tumor suppressor.\",\n      \"evidence\": \"RT-PCR, sequencing and qRT-PCR of matched oral squamous cell carcinoma tumor/normal pairs\",\n      \"pmids\": [\"20131318\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mutations not functionally reconstituted\", \"No biochemical validation of mutant effects on HAT targeting\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified INCA1 as the partner required for ING5's growth-suppressive output, showing the antiproliferative function is not cell-autonomous to ING5 alone.\",\n      \"evidence\": \"Yeast two-hybrid plus genetic epistasis in Inca1-/- MEFs and bone marrow with phenotypic readouts\",\n      \"pmids\": [\"21750715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which INCA1 enables ING5 function unknown\", \"No structural basis for the interaction\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a DNA-damage-specific role by showing ING5 is a Tip60 cofactor for p53-K120 acetylation, distinguishing it from the earlier p300/K382 pathway and routing p53 toward apoptotic targets.\",\n      \"evidence\": \"Co-IP, ChIP, K120R mutagenesis and siRNA in human cells\",\n      \"pmids\": [\"23576563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DNA damage triggers trimeric complex assembly not established\", \"Site selectivity vs hMOF mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected ING5 to cell-cycle control by showing CDK2 phosphorylates T152 within its NLS, while also demonstrating p53-independent proliferation effects.\",\n      \"evidence\": \"In vitro kinase assay, phospho-specific antibody, mutagenesis and siRNA cell-cycle analysis\",\n      \"pmids\": [\"25860957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"T152 phosphorylation alone does not alter localization—functional consequence unclear\", \"Identity of the p53-independent effector pathway unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established ING5 as the targeting subunit of HBO1/MOZ/MORF HAT complexes and its PHD-H3K4me3 reading as required for glioblastoma stem cell self-renewal, defining the chromatin-recruitment mechanism.\",\n      \"evidence\": \"PHD-domain mutant analysis, sphere formation assays and western blot in BTICs\",\n      \"pmids\": [\"28925404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway activation measured by western blot without complex reconstitution\", \"Direct chromatin targets in stem cells not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed ING5 promotes p300 autoacetylation at specific HAT-domain lysines to stimulate its enzymatic activity, providing a biochemical basis for ING5-driven p53/histone acetylation.\",\n      \"evidence\": \"SILAC acetylome mass spectrometry with site mapping and C646 inhibitor rescue\",\n      \"pmids\": [\"29416718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ING5 directly contacts the p300 HAT domain not shown\", \"Stoichiometry of activation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated ING5 loss activates EGFR/PI3K/Akt and IL-6/STAT3 signaling to drive EMT and metastasis, establishing ING5 as a restraint on oncogenic signaling.\",\n      \"evidence\": \"Phospho-kinase array, shRNA, pharmacological rescue and xenograft metastasis model\",\n      \"pmids\": [\"28903339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway activation inferred from phosphorylation changes only\", \"Link between chromatin function and signaling suppression unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved ING5 quaternary structure, showing N-terminal coiled-coil-mediated homo/heterodimerization, central dsDNA binding, and PHD reading of H3K4me3, and linking cancer mutations to coiled-coil destabilization.\",\n      \"evidence\": \"NMR, X-ray crystallography, SEC, DNA-binding assays and mutagenesis with cell cycle analysis\",\n      \"pmids\": [\"31026448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of ING4 heterodimerization vs homodimerization undefined\", \"How dimerization couples to HAT complex assembly unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed ING5 genetically as a co-regulator of self-renewal with Set1A/COMPASS, identifying it as a dependency of catalytically dead COMPASS in ESCs.\",\n      \"evidence\": \"Genome-wide CRISPR dropout screen in Set1A-ΔSET knock-in ESCs with gene expression\",\n      \"pmids\": [\"35500115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical link between ING5 and COMPASS shown\", \"Mechanism of synthetic lethality unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the upstream transcriptional control of ING5 itself, showing SRF and YY1 directly activate its promoter as an SRF-YY1-ING5-p53 complex.\",\n      \"evidence\": \"EMSA, ChIP, luciferase reporter and Co-IP in gastric cancer cells\",\n      \"pmids\": [\"35747809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling SRF/YY1 occupancy not defined\", \"Functional role of p53 within the promoter complex unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Used the Drosophila ortholog to show TCTP gates Ing5 nuclear translocation and MOZ/MORF chromatin binding, identifying a regulatory switch on H3K23 acetylation and EGFR/Yorkie signaling.\",\n      \"evidence\": \"Yeast two-hybrid, in vivo genetics, H3K23ac ChIP and epistasis in Drosophila\",\n      \"pmids\": [\"37014852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of TCTP regulation in mammals not tested\", \"Mechanism of TCTP-mediated nuclear exclusion unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined an ING5→miR-34c-5p→Snail1 axis suppressing TGF-β/Smad3-driven EMT, providing a transcriptional/post-transcriptional route for metastasis suppression.\",\n      \"evidence\": \"Overexpression, dual-luciferase 3'UTR validation, TGF-β inhibitor and xenograft model\",\n      \"pmids\": [\"37249332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ING5→miR-34c-5p linkage shown by overexpression only\", \"Direct chromatin mechanism for miR-34c-5p induction not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ING5 supports fetal liver hematopoiesis cell-extrinsically, refining its tissue-level role apart from intrinsic stem-cell function.\",\n      \"evidence\": \"Ing5-null mice, flow cytometry and competitive bone-marrow transplantation\",\n      \"pmids\": [\"37275850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-extrinsic mediator not identified\", \"Niche cell type responsible undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established ING4/ING5 as essential, non-redundant components of KAT6A/KAT6B/KAT7 complexes required for H3K14ac and H3K23ac in vivo, tying epigenetic marks to specific developmental phenotypes.\",\n      \"evidence\": \"Knockout mouse genetics, histone-mark western blot, transcriptomics and developmental phenotyping\",\n      \"pmids\": [\"38446206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gene-specific targeting rules of ING5 within these complexes unclear\", \"Basis of tissue-specific phenotypes (heart) not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a metabolic tumor-suppressive mechanism: ING5 induces TIE1 to phosphorylate PDK1-Y163, activating PDHA1 and shifting cells from glycolysis to oxidative phosphorylation to suppress invasion.\",\n      \"evidence\": \"SILAC phosphoproteomics, PDK1-Y163F mutagenesis, metabolic assays and xenografts\",\n      \"pmids\": [\"39269568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ING5 chromatin function induces TIE1 not shown\", \"Generality beyond lung cancer untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided in vivo proof of ING5 tumor suppression and genome maintenance, showing knockout mice develop lymphoma and KO MEFs accumulate in G2 with elevated DNA damage.\",\n      \"evidence\": \"CRISPR knockout mice, tumor pathology and flow cytometry for cell cycle/γH2AX\",\n      \"pmids\": [\"39787145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cause of γH2AX accumulation not defined\", \"Link between HAT-complex function and genome stability unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked ING5 (via MORF/Kat6b/Brpf1) to chromatin topology, showing it antagonizes CTCF/cohesin-mediated transcriptional insulation at developmental genes.\",\n      \"evidence\": \"Genome-wide CRISPR screen, acute depletion, Hi-C and Kat6b inhibition in ESCs (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.21.639596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ING5-specific role inferred from complex membership\", \"Preprint, single lab; direct ING5 contribution to insulation not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ING5's PHD/H3K4me3 reading and HAT-complex targeting mechanistically connect to its downstream signaling, metabolic, and genome-stability outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking chromatin function to EGFR/STAT3/Wnt and TIE1-PDK1 axes\", \"Mammalian regulators of ING5 nuclear localization beyond CDK2 unknown\", \"Genomic targets directing ING5/HAT acetylation in each tissue not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5, 6, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 9, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 14]}\n    ],\n    \"complexes\": [\n      \"HBO1 HAT complex\",\n      \"MOZ/MORF (KAT6) HAT complex\",\n      \"KAT7 HAT complex\"\n    ],\n    \"partners\": [\n      \"p300\",\n      \"TP53\",\n      \"KAT5\",\n      \"INCA1\",\n      \"ING4\",\n      \"CDK2\",\n      \"TCTP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}