{"gene":"ING4","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2003,"finding":"ING4 (p29ING4) physically interacts with p300 (a histone acetyltransferase complex component) 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, p21/WAF1 promoter reporter assay, colony formation, flow cytometry","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in vivo, promoter assay, and functional readouts; replicated by multiple subsequent studies","pmids":["12750254"],"is_preprint":false},{"year":2004,"finding":"ING4 physically interacts with the p65 (RelA) subunit of NF-κB and represses transcription of NF-κB-responsive genes, thereby regulating brain tumor angiogenesis.","method":"Co-immunoprecipitation, xenograft tumor model, gene expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus in vivo xenograft functional validation; widely replicated","pmids":["15029197"],"is_preprint":false},{"year":2004,"finding":"Overexpression of ING4 causes G2/M cell cycle arrest and upregulates p21 and Bax in a p53-dependent manner in HepG2 cells, and enhances chemosensitivity to etoposide and doxorubicin.","method":"Flow cytometry, Western blot, colony formation assay in p53-deficient (Saos-2) vs. p53-proficient (HepG2) cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function/gain-of-function with defined p53-dependent phenotype, single lab","pmids":["15251430"],"is_preprint":false},{"year":2005,"finding":"ING4 directly associates with the HIF prolyl hydroxylase (PHD/HPH) and represses HIF transcriptional activity without affecting HIF protein stability, providing a mechanism for ING4 regulation of the hypoxic response.","method":"Co-immunoprecipitation, HIF transcriptional reporter assay, protein stability analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP demonstrating physical association, functional reporter assay, replicated in multiple myeloma study","pmids":["15897452"],"is_preprint":false},{"year":2005,"finding":"The nuclear localization signal (NLS) region of ING4 is essential for its binding to p53; mutations or deletion of the NLS disrupt the ING4–p53 interaction in vitro and in vivo and abolish p21 upregulation.","method":"GST pulldown, co-immunoprecipitation, NLS mutagenesis, subcellular localization imaging","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — GST pulldown plus mutagenesis with functional readout, single lab","pmids":["15882981"],"is_preprint":false},{"year":2006,"finding":"The ING4 PHD finger structure was determined by NMR; ING4 PHD binds histone H3 trimethylated at K4 (H3K4me3) but, unlike ING2, does not bind phosphoinositides.","method":"NMR structure determination, binding assays with methylated histone peptides and phosphoinositides","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with direct binding characterization, replicated by subsequent structural studies","pmids":["17157298"],"is_preprint":false},{"year":2006,"finding":"ING4 splice variants lacking a full NLS show increased cytoplasmic localization, attenuated p21/WAF1 promoter activation, and altered cell spreading and migration suppression; ING4_v4 acts as a dominant-negative for p21 induction and cell motility suppression. ING4 variants also bind differentially to cytoplasmic proteins liprin-α1 and G3BP2a.","method":"Subcellular localization imaging, p21 promoter reporter assay, cell migration/spreading assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (imaging, reporter, migration assay, Co-IP), single lab","pmids":["16973615"],"is_preprint":false},{"year":2007,"finding":"ING4 directly interacts with HIF prolyl hydroxylase 2 (HPH-2/PHD2), suppresses HIF-1α activity and its target gene expression (NIP-3), and thereby reduces IL-8 and OPN proangiogenic molecule production in multiple myeloma cells.","method":"Co-immunoprecipitation, HIF reporter assay, siRNA knockdown, in vitro tube formation assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct interaction plus functional siRNA knockdown, single lab","pmids":["17848618"],"is_preprint":false},{"year":2007,"finding":"ING4 is expressed in ROMK-positive renal tubules; ING4 expression increases p38 and ERK MAPK phosphorylation, and ING4 reduces renal outer medullary K+ (ROMK) channel current in Xenopus oocytes through MAPK stimulation in response to low dietary K+ intake.","method":"siRNA knockdown, Western blot for phospho-MAPK, Xenopus oocyte electrophysiology, immunocytochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional electrophysiology plus siRNA knockdown and imaging, single lab","pmids":["17517644"],"is_preprint":false},{"year":2008,"finding":"ING4 and NF-κB bind simultaneously at NF-κB-regulated promoters; ING4 does not prevent NF-κB activation, nuclear translocation, or DNA binding but reduces p65 phosphorylation, p300, acetylated histones, and H3Me3K4 levels at target promoters while enhancing HDAC-1 recruitment.","method":"Chromatin immunoprecipitation (ChIP), Co-IP, siRNA knockdown, reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus Co-IP plus knockdown with defined chromatin-level mechanism, multiple orthogonal methods","pmids":["18779315"],"is_preprint":false},{"year":2008,"finding":"ING4 overexpression suppresses melanoma cell migration by ~63% and inhibits RhoA GTPase activity and ROCK-mediated stress fiber formation, and inhibits invasion by ~43% with reduced MMP-2 and MMP-9 activity.","method":"Cell migration/invasion assay, RhoA GTPase activity assay, zymography for MMP-2/9, overexpression","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with defined pathway (RhoA/ROCK), single lab","pmids":["18375955"],"is_preprint":false},{"year":2008,"finding":"ING4 splice variant localization is modulated by two wobble-splicing events at the exon 4–5 boundary; ING4_v1 localizes to the nucleolus (containing an intrinsic nucleolar localization signal), and nucleolar accumulation prolongs ING4 half-life. ING4 is degraded via the ubiquitin-proteasome pathway and subjected to N-terminal ubiquitination.","method":"Subcellular localization imaging, protein half-life assay, proteasome inhibitor treatment, ubiquitination assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence (stability), single lab, multiple methods","pmids":["18775696"],"is_preprint":false},{"year":2009,"finding":"ING4 is a native subunit of the HBO1 histone acetyltransferase (HAT) complex. The ING4 PHD finger specifically recognizes H3K4me3, and this interaction augments HBO1 acetyltransferase activity on H3 tails and drives H3 acetylation at ING4 target promoters. ING4–H3K4me3 interaction is required for ING4-dependent apoptosis after genotoxic stress and inhibition of anchorage-independent growth.","method":"Co-immunoprecipitation, in vitro HAT assay, ChIP, PHD finger mutagenesis, anchorage-independent growth assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro HAT assay reconstitution plus ChIP plus mutagenesis plus functional cellular assays, multiple orthogonal methods","pmids":["19187765"],"is_preprint":false},{"year":2010,"finding":"ING4 forms homodimers through its N-terminal coiled-coil domain; the dimer has two independent H3K4me3-binding PHD fingers, suggesting bivalent chromatin recognition to enhance HBO1 complex targeting. Monomeric ING4 mutants lose the ability to induce apoptosis after genotoxic stress.","method":"NMR of full-length protein, analytical ultracentrifugation, H3K4me3 binding assay, dimerization mutagenesis, apoptosis assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural analysis combined with mutagenesis and functional apoptosis assay, rigorous study","pmids":["20053357"],"is_preprint":false},{"year":2010,"finding":"ING4 expression is induced by the metastasis suppressor BRMS1; ING4 knockdown abrogates BRMS1-mediated suppression of HUVEC growth and IL-6 expression, placing ING4 downstream of BRMS1 in the suppression of melanoma angiogenesis via NF-κB/IL-6 axis.","method":"siRNA knockdown, epistasis by rescue experiments, HUVEC tube formation assay, in vivo matrigel plug assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via rescue experiments, in vitro and in vivo functional assays, single lab","pmids":["21056991"],"is_preprint":false},{"year":2011,"finding":"PAD4 citrullinates ING4 preferentially within its NLS region, disrupting the ING4–p53 interaction. A citrulline-mimicking Arg→Gln NLS mutant of ING4 loses p53 binding, fails to promote p53 acetylation, represses p21 expression, and is more susceptible to proteasomal degradation.","method":"In vitro citrullination assay, Co-IP, site-directed mutagenesis, Western blot for p21/acetylated p53, protein stability assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay plus mutagenesis plus Co-IP plus functional downstream readout, multiple orthogonal methods in one study","pmids":["21454715"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the ING4 N-terminal dimerization domain reveals an antiparallel coiled-coil homodimer with helix-loop-helix protomers. Monomeric mutants lose the ability to induce apoptosis after genotoxic stress, demonstrating that dimerization is functionally required for tumor suppressor activity.","method":"X-ray crystallography (2.3 Å resolution), dimerization mutagenesis, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis validation, single rigorous study with multiple methods","pmids":["22334692"],"is_preprint":false},{"year":2012,"finding":"ING4 negatively regulates NF-κB in breast cancer by inhibiting p65/RelA phosphorylation; ectopic ING4 expression suppresses PMA-induced invasion and NF-κB target gene expression in T47D and MCF7 breast cancer cells.","method":"Ectopic overexpression, Western blot for phospho-p65, invasion assay, gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with defined phosphorylation and functional readouts, single lab","pmids":["23056468"],"is_preprint":false},{"year":2013,"finding":"ING4 binds directly to AUF1; the ING4–AUF1 complex associates with MYC mRNA (shown by mRNP immunoprecipitation), and ING4 suppresses MYC protein expression without altering MYC mRNA levels, indicating translational repression.","method":"Co-immunoprecipitation, mRNP immunoprecipitation, Western blot, qRT-PCR","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mRNP-IP plus orthogonal mRNA vs. protein comparison, single lab","pmids":["23603392"],"is_preprint":false},{"year":2013,"finding":"ING4 regulates a chemokine secretory phenotype in primary fibroblasts in a p53-dependent and H3K4me3-recognition-dependent manner; this phenotype selectively promotes tumor cell proliferation in a paracrine fashion in vitro and promotes tumor growth in co-injection in vivo assays.","method":"Gene expression analysis, PHD finger mutant, p53 dependency, in vitro co-culture proliferation, in vivo co-injection xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (mutagenesis, in vivo co-injection), single lab","pmids":["23604125"],"is_preprint":false},{"year":2013,"finding":"HPV16 E6 oncoprotein binds ING4 in vivo and in vitro, attenuating ING4-induced p53 acetylation and the ING4–p53 interaction independently of p53 degradation, thereby diminishing ING4-enhanced p53-mediated apoptosis.","method":"Co-immunoprecipitation (in vivo and in vitro), p53 acetylation Western blot, apoptosis assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in vivo and in vitro plus functional apoptosis readout, single lab","pmids":["23967213"],"is_preprint":false},{"year":2014,"finding":"ING4 expression is transiently induced by Myc during prostate epithelial differentiation from basal to luminal cells; Pten loss blocks ING4 expression, and re-expression of ING4 rescues Pten-loss-induced differentiation defects. Loss of ING4 (directly or via Pten loss) prevents luminal differentiation and promotes tumorigenesis downstream of Myc.","method":"Genetic epistasis (Pten KO rescue by ING4 re-expression), 3D organoid differentiation assay, tumor xenograft, IHC of human tumors","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined phenotypic rescue, multiple models, single lab","pmids":["24762396"],"is_preprint":false},{"year":2015,"finding":"JFK is an F-box protein that targets ING4 for ubiquitination and proteasomal degradation by assembling an SCF(JFK) E3 ubiquitin ligase complex. JFK-mediated ING4 destabilization leads to hyperactivation of canonical NF-κB signaling and promotes breast cancer angiogenesis and metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, siRNA knockdown, in vivo metastasis model","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical reconstitution of E3 ligase activity plus ubiquitination assay plus in vivo functional validation, multiple orthogonal methods","pmids":["25792601"],"is_preprint":false},{"year":2015,"finding":"ING4 inhibits estrogen-independent ER activity in breast cancer cells; ING4 overexpression represses selective ER-target gene transcription without affecting nuclear ERα protein levels, and increases sensitivity of ER+ cells to hormone deprivation.","method":"ER-target gene expression analysis, hormone deprivation assay, overexpression in T47D and MCF7 cells, fulvestrant vs. tamoxifen comparison","journal":"Breast cancer (Dove Medical Press)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with gene expression readout, no direct binding/chromatin assay, single lab","pmids":["27895513"],"is_preprint":false},{"year":2019,"finding":"ING4 suppresses HCC growth and metastasis via a NF-κB/miR-155/FOXO3a pathway: ING4 represses NF-κB transcriptional activity, thereby reducing miR-155 expression, which relieves miR-155-mediated suppression of FOXO3a, increasing FOXO3a nuclear level and transcriptional activity.","method":"Lentiviral overexpression and knockdown, luciferase reporter for NF-κB, miR-155 overexpression/inhibition rescue experiments, in vivo xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue experiments with multiple pathway interventions, in vitro and in vivo, single lab","pmids":["30745827"],"is_preprint":false},{"year":2019,"finding":"ING4 localizes strongly to the nucleolus via its PHD domain (which binds H3K4me3 at active rDNA promoters); ING4-deficient cells show reduced H3K9 acetylation and UBF occupancy at rDNA promoters, reduced rRNA transcription, and altered nucleolar structure, all rescued by GFP-ING4 re-expression.","method":"Immunofluorescence/nucleolar localization, CRISPR/RNAi-mediated ING4 deficiency, ChIP for H3K9ac and UBF, rRNA transcription assay, rescue by re-expression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional rescue, direct localization with functional consequence, single lab","pmids":["31754246"],"is_preprint":false},{"year":2020,"finding":"ING4 directly interacts with SIRT1 (shown by immunoprecipitation) and blocks NF-κB p65 nuclear translocation and p65 acetylation at K310 in LPS-stimulated macrophages, providing an anti-inflammatory mechanism via an ING4/SIRT1/NF-κB axis.","method":"Co-immunoprecipitation, Western blot for nuclear p65 and acetyl-p65 K310, LPS macrophage model in vitro and in vivo","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct interaction plus functional downstream readout, single lab","pmids":["31811786"],"is_preprint":false},{"year":2021,"finding":"Cxcl10-induced migration of ING4-deleted breast cancer cells requires a physical or proximal association between Cxcr3 and Egfr receptors (shown by immunofluorescent colocalization) and downstream Gβγ signaling; ING4-intact cells do not sustain the Cxcr3/Egfr colocalization or migration response.","method":"Immunofluorescent receptor colocalization, pharmacological inhibitors of Cxcr3/Egfr/Gβγ, ING4-deletion cell line, cell migration assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor colocalization plus pharmacological epistasis, single lab","pmids":["34871062"],"is_preprint":false},{"year":2023,"finding":"CK2 (casein kinase 2) phosphorylates ING4 at Ser-150, triggering ING4 ubiquitination and degradation by the JFK E3 ubiquitin ligase. CK2 knockout increases ING4 protein stability and enhances T cell anti-tumor activity by allowing ING4-dependent PD-L1 autophagic degradation, thereby suppressing NSCLC immune escape.","method":"CK2 knockout, phospho-site mapping (ING4-S150), ubiquitination assay, protein stability assay, PD-L1 expression/autophagic degradation assay, T cell co-culture assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site identification plus ubiquitination assay plus functional immune escape readout, single lab","pmids":["37870169"],"is_preprint":false},{"year":2024,"finding":"ING4 and ING5 are essential components of the KAT6A/KAT6B/KAT7 HAT complexes required for histone H3K14 acetylation and H3K23 acetylation; Ing4/Ing5 double-knockout embryos show loss of H3K14ac and reduced H3K23ac. ING4/ING5 are required for epicardial cell lineage development and proepicardium outgrowth, with Ing4+/−Ing5−/− hearts showing epicardial and coronary vasculature defects.","method":"Mouse knockout genetics, histone modification Western blot/ChIP, cardiac phenotype analysis, cell adhesion gene expression","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with direct histone modification measurement and defined developmental phenotype, multiple genotypes tested","pmids":["38446206"],"is_preprint":false},{"year":2024,"finding":"Ing4 deficiency in hematopoietic stem cells (HSCs) promotes a transcriptionally poised state with gene expression signatures of activation yet G0 arrest; Ing4-deficient HSCs show enhanced regenerative capacity after transplantation, indicating ING4 regulates HSC quiescence and self-renewal balance.","method":"Mouse Ing4 knockout, transcriptome analysis, cell cycle analysis (G0 markers), competitive transplantation assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with transcriptomics and functional transplantation readout, single lab","pmids":["39175773"],"is_preprint":false},{"year":2010,"finding":"A cancer-associated ING4 mutant (N214D) found in human tumors shows dramatically reduced ability to inhibit proliferation, anchorage-independent growth, and cell migration, and sensitize to cell death; the functional impairment correlates with reduced protein stability due to increased proteasome-mediated degradation, not with altered H3K4me3 binding or folding.","method":"Mutagenesis, protein stability assay, proteasome inhibitor rescue, proliferation/migration/soft agar assays, histone binding assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis with multiple orthogonal functional and biochemical assays, single lab","pmids":["20705953"],"is_preprint":false}],"current_model":"ING4 is a tumor suppressor that functions as a native subunit of the HBO1/KAT7 histone acetyltransferase complex, where its PHD finger reads the H3K4me3 chromatin mark to recruit the complex to target promoters and drive H3 acetylation; it forms homodimers via an N-terminal coiled-coil domain enabling bivalent H3K4me3 recognition, interacts with p53 (via its NLS region) to enhance p53 acetylation and transcriptional activity, directly binds and represses NF-κB (p65/RelA) at target promoters by modulating histone acetylation and HDAC-1 recruitment, associates with HIF prolyl hydroxylases to repress HIF transcriptional activity, inhibits MYC translation by associating with AUF1, and promotes rRNA transcription in the nucleolus; its protein stability is regulated by CK2-mediated phosphorylation at Ser-150 followed by SCF(JFK)-mediated ubiquitination and proteasomal degradation, and its activity can be further modulated by PAD4-mediated citrullination of the NLS, which disrupts p53 binding."},"narrative":{"mechanistic_narrative":"ING4 is a chromatin-reading tumor suppressor that couples recognition of the H3K4me3 active-promoter mark to histone acetyltransferase activity and to the control of multiple transcriptional programs governing growth, apoptosis, angiogenesis, and differentiation [PMID:19187765, PMID:17157298]. It functions as a native subunit of the HBO1 (KAT7) histone acetyltransferase complex, where its PHD finger specifically binds H3K4me3 to augment HBO1-driven H3 acetylation at target promoters, an interaction required for ING4-dependent apoptosis after genotoxic stress and for suppression of anchorage-independent growth [PMID:19187765]; ING4 and the paralog ING5 are similarly essential for H3K14 and H3K23 acetylation by KAT6A/KAT6B/KAT7 complexes during epicardial lineage development [PMID:38446206]. ING4 homodimerizes through an N-terminal antiparallel coiled-coil, presenting two independent H3K4me3-binding PHD fingers for bivalent chromatin recognition, and disruption of dimerization abolishes its pro-apoptotic activity [PMID:20053357, PMID:22334692]. Beyond the acetyltransferase complex, ING4 enhances p53 acetylation and p53-dependent p21 induction and apoptosis through an interaction requiring its NLS region [PMID:12750254, PMID:15882981], and directly binds NF-κB p65/RelA to repress NF-κB target genes at the chromatin level by lowering p300 recruitment, histone acetylation and H3K4me3 while promoting HDAC-1 recruitment, thereby restraining tumor angiogenesis [PMID:15029197, PMID:18779315]. It additionally represses HIF transcriptional activity via association with HIF prolyl hydroxylases independently of HIF stability [PMID:15897452, PMID:17848618], represses MYC at the translational level by binding AUF1 on MYC mRNA [PMID:23603392], and drives rRNA transcription in the nucleolus through PHD-dependent localization to active rDNA promoters [PMID:31754246]. ING4 abundance is controlled by CK2-mediated phosphorylation at Ser-150 that licenses SCF(JFK)-mediated ubiquitination and proteasomal degradation [PMID:25792601, PMID:37870169], and its p53-activating function is further modulated by PAD4-mediated citrullination of the NLS, which disrupts p53 binding [PMID:21454715].","teleology":[{"year":2003,"claim":"Established ING4 as a p53 cofactor, answering whether it acts through a defined transcriptional partner to enforce growth arrest and apoptosis.","evidence":"Co-IP with p300 and p53, p21/WAF1 reporter, and apoptosis/colony assays","pmids":["12750254"],"confidence":"High","gaps":["Did not map the ING4 region required for p53 binding","Did not establish whether p53 enhancement occurs within a HAT complex"]},{"year":2004,"claim":"Identified NF-κB p65/RelA as a second direct target and linked ING4 to suppression of tumor angiogenesis, broadening its role beyond p53.","evidence":"Co-IP with p65, gene expression analysis, and brain tumor xenograft","pmids":["15029197"],"confidence":"High","gaps":["Chromatin-level mechanism of repression not yet defined","Relationship to the p53 pathway unresolved"]},{"year":2005,"claim":"Defined the NLS region as the p53-binding determinant and showed ING4 represses HIF transcriptional activity via prolyl hydroxylase association, expanding its target repertoire to the hypoxic response.","evidence":"GST pulldown and NLS mutagenesis for p53; Co-IP with PHD/HPH and HIF reporter with stability controls","pmids":["15882981","15897452"],"confidence":"Medium","gaps":["Single-lab NLS mapping","Did not resolve whether HIF repression is direct or chromatin-mediated"]},{"year":2006,"claim":"Provided the structural basis for chromatin reading by ING4, answering how it is targeted to active promoters and distinguishing it from the phosphoinositide-binding ING2.","evidence":"NMR structure of the PHD finger with methylated histone and phosphoinositide binding assays","pmids":["17157298"],"confidence":"High","gaps":["Did not connect H3K4me3 reading to a specific enzymatic complex","Functional consequence of reading not yet shown"]},{"year":2008,"claim":"Resolved how ING4 represses NF-κB without blocking its activation: it remodels the chromatin environment at target promoters rather than preventing p65 DNA binding.","evidence":"ChIP, Co-IP, and siRNA showing reduced p300/acetyl-histone/H3K4me3 and increased HDAC-1 at promoters","pmids":["18779315"],"confidence":"High","gaps":["Did not identify the acetyltransferase complex delivering ING4 to these promoters","Splice-variant and localization control addressed separately"]},{"year":2009,"claim":"Unified the chromatin-reading and acetylation activities by showing ING4 is a native HBO1 HAT subunit whose PHD-H3K4me3 engagement augments H3 acetylation and is required for genotoxic apoptosis.","evidence":"Co-IP, in vitro HAT reconstitution, ChIP, PHD mutagenesis, and anchorage-independent growth assay","pmids":["19187765"],"confidence":"High","gaps":["Stoichiometry and architecture of ING4 within the complex not defined","Did not address dimerization"]},{"year":2012,"claim":"Defined the oligomeric architecture of ING4, showing an antiparallel coiled-coil homodimer that presents two PHD fingers for bivalent recognition and is functionally required for apoptosis.","evidence":"NMR of full-length protein, analytical ultracentrifugation, crystal structure of the dimerization domain, and dimerization mutant apoptosis assays","pmids":["20053357","22334692"],"confidence":"High","gaps":["Did not show bivalent engagement on nucleosomal arrays","Link between dimerization and HBO1 targeting inferred, not directly measured"]},{"year":2013,"claim":"Extended ING4 mechanism to post-transcriptional and paracrine control, showing translational MYC repression via AUF1 and an H3K4me3/p53-dependent fibroblast secretory phenotype affecting tumor growth.","evidence":"Co-IP and mRNP-IP with AUF1 on MYC mRNA; PHD-mutant and p53-dependency assays with co-injection xenografts","pmids":["23603392","23604125"],"confidence":"Medium","gaps":["AUF1-MYC mechanism not reconstituted","Paracrine secretory program direction (tumor-promoting vs suppressing) context-dependent"]},{"year":2015,"claim":"Identified the degradation machinery for ING4, showing SCF(JFK) ubiquitinates and destabilizes it and that this destabilization hyperactivates NF-κB to drive metastasis.","evidence":"Co-IP, in vitro ubiquitination, stability assays, and in vivo metastasis model","pmids":["25792601"],"confidence":"High","gaps":["Upstream signal triggering JFK targeting not defined here","Degradation site not yet mapped"]},{"year":2019,"claim":"Connected ING4 chromatin function to ribosome biogenesis, showing PHD-dependent nucleolar localization at active rDNA promotes H3K9ac, UBF occupancy, and rRNA transcription.","evidence":"Immunofluorescence, CRISPR/RNAi deficiency, ChIP for H3K9ac/UBF, and rescue by re-expression","pmids":["31754246"],"confidence":"Medium","gaps":["Whether HBO1/KAT complex mediates rDNA acetylation not shown","Single-lab finding"]},{"year":2024,"claim":"Established physiological developmental and stem-cell roles, showing ING4/ING5 are required for KAT6/KAT7-dependent H3K14/H3K23 acetylation in cardiac development and that ING4 regulates HSC quiescence and self-renewal.","evidence":"Mouse Ing4/Ing5 knockout genetics with histone modification ChIP/Western, cardiac phenotyping, HSC transcriptomics and competitive transplantation","pmids":["38446206","39175773"],"confidence":"High","gaps":["Direct in vivo target promoters of ING4 in these tissues not catalogued","Mechanism linking ING4 loss to the HSC poised state undefined"]},{"year":2023,"claim":"Resolved the kinase signal upstream of ING4 degradation and a new functional consequence, showing CK2 phosphorylation at Ser-150 licenses JFK-mediated degradation and that stabilized ING4 promotes PD-L1 autophagic clearance to limit immune escape.","evidence":"CK2 knockout, phospho-site mapping, ubiquitination/stability assays, PD-L1 degradation and T-cell co-culture assays","pmids":["37870169"],"confidence":"Medium","gaps":["Mechanism linking ING4 to PD-L1 autophagy not molecularly defined","Single-lab finding"]},{"year":null,"claim":"How ING4's distinct activities — HBO1/KAT-complex acetylation, p53 cofactor function, NF-κB repression, and nucleolar rRNA control — are coordinated and prioritized in a given cell state remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genome-wide map distinguishing direct ING4-HBO1 targets from p53/NF-κB-dependent ones","Quantitative partitioning of ING4 among its protein partners unknown","No human Mendelian disease link established in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[5,12,13,25]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,9,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,9]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6,9]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[11,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,9,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,9,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2,12,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[22,28,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[29,21,30]}],"complexes":["HBO1/KAT7 histone acetyltransferase complex","KAT6A/KAT6B/KAT7 HAT complex","SCF(JFK) E3 ubiquitin ligase complex"],"partners":["TP53","RELA","EP300","EGLN1","AUF1","SIRT1","KAT7","JFK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UNL4","full_name":"Inhibitor of growth protein 4","aliases":["p29ING4"],"length_aa":249,"mass_kda":28.5,"function":"Component of HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), and have reduced activity toward histone H4 (PubMed:16387653). Through chromatin acetylation it may function in DNA replication (PubMed:16387653). May inhibit tumor progression by modulating the transcriptional output of signaling pathways which regulate cell proliferation (PubMed:15251430, PubMed:15528276). Can suppress brain tumor angiogenesis through transcriptional repression of RELA/NFKB3 target genes when complexed with RELA (PubMed:15029197). May also specifically suppress loss of contact inhibition elicited by activated oncogenes such as MYC (PubMed:15029197). Represses hypoxia inducible factor's (HIF) activity by interacting with HIF prolyl hydroxylase 2 (EGLN1) (PubMed:15897452). 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Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/20445261","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50286,"output_tokens":7364,"usd":0.130659,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16584,"output_tokens":4469,"usd":0.097323,"stage2_stop_reason":"end_turn"},"total_usd":0.227982,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"ING4 (p29ING4) physically interacts with p300 (a histone acetyltransferase complex component) 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, p21/WAF1 promoter reporter assay, colony formation, flow cytometry\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in vivo, promoter assay, and functional readouts; replicated by multiple subsequent studies\",\n      \"pmids\": [\"12750254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ING4 physically interacts with the p65 (RelA) subunit of NF-κB and represses transcription of NF-κB-responsive genes, thereby regulating brain tumor angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, xenograft tumor model, gene expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus in vivo xenograft functional validation; widely replicated\",\n      \"pmids\": [\"15029197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Overexpression of ING4 causes G2/M cell cycle arrest and upregulates p21 and Bax in a p53-dependent manner in HepG2 cells, and enhances chemosensitivity to etoposide and doxorubicin.\",\n      \"method\": \"Flow cytometry, Western blot, colony formation assay in p53-deficient (Saos-2) vs. p53-proficient (HepG2) cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function/gain-of-function with defined p53-dependent phenotype, single lab\",\n      \"pmids\": [\"15251430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ING4 directly associates with the HIF prolyl hydroxylase (PHD/HPH) and represses HIF transcriptional activity without affecting HIF protein stability, providing a mechanism for ING4 regulation of the hypoxic response.\",\n      \"method\": \"Co-immunoprecipitation, HIF transcriptional reporter assay, protein stability 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 — direct Co-IP demonstrating physical association, functional reporter assay, replicated in multiple myeloma study\",\n      \"pmids\": [\"15897452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The nuclear localization signal (NLS) region of ING4 is essential for its binding to p53; mutations or deletion of the NLS disrupt the ING4–p53 interaction in vitro and in vivo and abolish p21 upregulation.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, NLS mutagenesis, subcellular localization imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — GST pulldown plus mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"15882981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The ING4 PHD finger structure was determined by NMR; ING4 PHD binds histone H3 trimethylated at K4 (H3K4me3) but, unlike ING2, does not bind phosphoinositides.\",\n      \"method\": \"NMR structure determination, binding assays with methylated histone peptides and phosphoinositides\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with direct binding characterization, replicated by subsequent structural studies\",\n      \"pmids\": [\"17157298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ING4 splice variants lacking a full NLS show increased cytoplasmic localization, attenuated p21/WAF1 promoter activation, and altered cell spreading and migration suppression; ING4_v4 acts as a dominant-negative for p21 induction and cell motility suppression. ING4 variants also bind differentially to cytoplasmic proteins liprin-α1 and G3BP2a.\",\n      \"method\": \"Subcellular localization imaging, p21 promoter reporter assay, cell migration/spreading assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (imaging, reporter, migration assay, Co-IP), single lab\",\n      \"pmids\": [\"16973615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ING4 directly interacts with HIF prolyl hydroxylase 2 (HPH-2/PHD2), suppresses HIF-1α activity and its target gene expression (NIP-3), and thereby reduces IL-8 and OPN proangiogenic molecule production in multiple myeloma cells.\",\n      \"method\": \"Co-immunoprecipitation, HIF reporter assay, siRNA knockdown, in vitro tube formation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct interaction plus functional siRNA knockdown, single lab\",\n      \"pmids\": [\"17848618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ING4 is expressed in ROMK-positive renal tubules; ING4 expression increases p38 and ERK MAPK phosphorylation, and ING4 reduces renal outer medullary K+ (ROMK) channel current in Xenopus oocytes through MAPK stimulation in response to low dietary K+ intake.\",\n      \"method\": \"siRNA knockdown, Western blot for phospho-MAPK, Xenopus oocyte electrophysiology, immunocytochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional electrophysiology plus siRNA knockdown and imaging, single lab\",\n      \"pmids\": [\"17517644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ING4 and NF-κB bind simultaneously at NF-κB-regulated promoters; ING4 does not prevent NF-κB activation, nuclear translocation, or DNA binding but reduces p65 phosphorylation, p300, acetylated histones, and H3Me3K4 levels at target promoters while enhancing HDAC-1 recruitment.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), Co-IP, siRNA knockdown, reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus Co-IP plus knockdown with defined chromatin-level mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"18779315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ING4 overexpression suppresses melanoma cell migration by ~63% and inhibits RhoA GTPase activity and ROCK-mediated stress fiber formation, and inhibits invasion by ~43% with reduced MMP-2 and MMP-9 activity.\",\n      \"method\": \"Cell migration/invasion assay, RhoA GTPase activity assay, zymography for MMP-2/9, overexpression\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with defined pathway (RhoA/ROCK), single lab\",\n      \"pmids\": [\"18375955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ING4 splice variant localization is modulated by two wobble-splicing events at the exon 4–5 boundary; ING4_v1 localizes to the nucleolus (containing an intrinsic nucleolar localization signal), and nucleolar accumulation prolongs ING4 half-life. ING4 is degraded via the ubiquitin-proteasome pathway and subjected to N-terminal ubiquitination.\",\n      \"method\": \"Subcellular localization imaging, protein half-life assay, proteasome inhibitor treatment, ubiquitination assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence (stability), single lab, multiple methods\",\n      \"pmids\": [\"18775696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ING4 is a native subunit of the HBO1 histone acetyltransferase (HAT) complex. The ING4 PHD finger specifically recognizes H3K4me3, and this interaction augments HBO1 acetyltransferase activity on H3 tails and drives H3 acetylation at ING4 target promoters. ING4–H3K4me3 interaction is required for ING4-dependent apoptosis after genotoxic stress and inhibition of anchorage-independent growth.\",\n      \"method\": \"Co-immunoprecipitation, in vitro HAT assay, ChIP, PHD finger mutagenesis, anchorage-independent growth assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro HAT assay reconstitution plus ChIP plus mutagenesis plus functional cellular assays, multiple orthogonal methods\",\n      \"pmids\": [\"19187765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ING4 forms homodimers through its N-terminal coiled-coil domain; the dimer has two independent H3K4me3-binding PHD fingers, suggesting bivalent chromatin recognition to enhance HBO1 complex targeting. Monomeric ING4 mutants lose the ability to induce apoptosis after genotoxic stress.\",\n      \"method\": \"NMR of full-length protein, analytical ultracentrifugation, H3K4me3 binding assay, dimerization mutagenesis, apoptosis assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural analysis combined with mutagenesis and functional apoptosis assay, rigorous study\",\n      \"pmids\": [\"20053357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ING4 expression is induced by the metastasis suppressor BRMS1; ING4 knockdown abrogates BRMS1-mediated suppression of HUVEC growth and IL-6 expression, placing ING4 downstream of BRMS1 in the suppression of melanoma angiogenesis via NF-κB/IL-6 axis.\",\n      \"method\": \"siRNA knockdown, epistasis by rescue experiments, HUVEC tube formation assay, in vivo matrigel plug assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via rescue experiments, in vitro and in vivo functional assays, single lab\",\n      \"pmids\": [\"21056991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PAD4 citrullinates ING4 preferentially within its NLS region, disrupting the ING4–p53 interaction. A citrulline-mimicking Arg→Gln NLS mutant of ING4 loses p53 binding, fails to promote p53 acetylation, represses p21 expression, and is more susceptible to proteasomal degradation.\",\n      \"method\": \"In vitro citrullination assay, Co-IP, site-directed mutagenesis, Western blot for p21/acetylated p53, protein stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay plus mutagenesis plus Co-IP plus functional downstream readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21454715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the ING4 N-terminal dimerization domain reveals an antiparallel coiled-coil homodimer with helix-loop-helix protomers. Monomeric mutants lose the ability to induce apoptosis after genotoxic stress, demonstrating that dimerization is functionally required for tumor suppressor activity.\",\n      \"method\": \"X-ray crystallography (2.3 Å resolution), dimerization mutagenesis, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis validation, single rigorous study with multiple methods\",\n      \"pmids\": [\"22334692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ING4 negatively regulates NF-κB in breast cancer by inhibiting p65/RelA phosphorylation; ectopic ING4 expression suppresses PMA-induced invasion and NF-κB target gene expression in T47D and MCF7 breast cancer cells.\",\n      \"method\": \"Ectopic overexpression, Western blot for phospho-p65, invasion assay, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with defined phosphorylation and functional readouts, single lab\",\n      \"pmids\": [\"23056468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ING4 binds directly to AUF1; the ING4–AUF1 complex associates with MYC mRNA (shown by mRNP immunoprecipitation), and ING4 suppresses MYC protein expression without altering MYC mRNA levels, indicating translational repression.\",\n      \"method\": \"Co-immunoprecipitation, mRNP immunoprecipitation, Western blot, qRT-PCR\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mRNP-IP plus orthogonal mRNA vs. protein comparison, single lab\",\n      \"pmids\": [\"23603392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ING4 regulates a chemokine secretory phenotype in primary fibroblasts in a p53-dependent and H3K4me3-recognition-dependent manner; this phenotype selectively promotes tumor cell proliferation in a paracrine fashion in vitro and promotes tumor growth in co-injection in vivo assays.\",\n      \"method\": \"Gene expression analysis, PHD finger mutant, p53 dependency, in vitro co-culture proliferation, in vivo co-injection xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (mutagenesis, in vivo co-injection), single lab\",\n      \"pmids\": [\"23604125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HPV16 E6 oncoprotein binds ING4 in vivo and in vitro, attenuating ING4-induced p53 acetylation and the ING4–p53 interaction independently of p53 degradation, thereby diminishing ING4-enhanced p53-mediated apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), p53 acetylation Western blot, apoptosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in vivo and in vitro plus functional apoptosis readout, single lab\",\n      \"pmids\": [\"23967213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ING4 expression is transiently induced by Myc during prostate epithelial differentiation from basal to luminal cells; Pten loss blocks ING4 expression, and re-expression of ING4 rescues Pten-loss-induced differentiation defects. Loss of ING4 (directly or via Pten loss) prevents luminal differentiation and promotes tumorigenesis downstream of Myc.\",\n      \"method\": \"Genetic epistasis (Pten KO rescue by ING4 re-expression), 3D organoid differentiation assay, tumor xenograft, IHC of human tumors\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined phenotypic rescue, multiple models, single lab\",\n      \"pmids\": [\"24762396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JFK is an F-box protein that targets ING4 for ubiquitination and proteasomal degradation by assembling an SCF(JFK) E3 ubiquitin ligase complex. JFK-mediated ING4 destabilization leads to hyperactivation of canonical NF-κB signaling and promotes breast cancer angiogenesis and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, siRNA knockdown, in vivo metastasis model\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical reconstitution of E3 ligase activity plus ubiquitination assay plus in vivo functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"25792601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ING4 inhibits estrogen-independent ER activity in breast cancer cells; ING4 overexpression represses selective ER-target gene transcription without affecting nuclear ERα protein levels, and increases sensitivity of ER+ cells to hormone deprivation.\",\n      \"method\": \"ER-target gene expression analysis, hormone deprivation assay, overexpression in T47D and MCF7 cells, fulvestrant vs. tamoxifen comparison\",\n      \"journal\": \"Breast cancer (Dove Medical Press)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with gene expression readout, no direct binding/chromatin assay, single lab\",\n      \"pmids\": [\"27895513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ING4 suppresses HCC growth and metastasis via a NF-κB/miR-155/FOXO3a pathway: ING4 represses NF-κB transcriptional activity, thereby reducing miR-155 expression, which relieves miR-155-mediated suppression of FOXO3a, increasing FOXO3a nuclear level and transcriptional activity.\",\n      \"method\": \"Lentiviral overexpression and knockdown, luciferase reporter for NF-κB, miR-155 overexpression/inhibition rescue experiments, in vivo xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue experiments with multiple pathway interventions, in vitro and in vivo, single lab\",\n      \"pmids\": [\"30745827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ING4 localizes strongly to the nucleolus via its PHD domain (which binds H3K4me3 at active rDNA promoters); ING4-deficient cells show reduced H3K9 acetylation and UBF occupancy at rDNA promoters, reduced rRNA transcription, and altered nucleolar structure, all rescued by GFP-ING4 re-expression.\",\n      \"method\": \"Immunofluorescence/nucleolar localization, CRISPR/RNAi-mediated ING4 deficiency, ChIP for H3K9ac and UBF, rRNA transcription assay, rescue by re-expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional rescue, direct localization with functional consequence, single lab\",\n      \"pmids\": [\"31754246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ING4 directly interacts with SIRT1 (shown by immunoprecipitation) and blocks NF-κB p65 nuclear translocation and p65 acetylation at K310 in LPS-stimulated macrophages, providing an anti-inflammatory mechanism via an ING4/SIRT1/NF-κB axis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for nuclear p65 and acetyl-p65 K310, LPS macrophage model in vitro and in vivo\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct interaction plus functional downstream readout, single lab\",\n      \"pmids\": [\"31811786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cxcl10-induced migration of ING4-deleted breast cancer cells requires a physical or proximal association between Cxcr3 and Egfr receptors (shown by immunofluorescent colocalization) and downstream Gβγ signaling; ING4-intact cells do not sustain the Cxcr3/Egfr colocalization or migration response.\",\n      \"method\": \"Immunofluorescent receptor colocalization, pharmacological inhibitors of Cxcr3/Egfr/Gβγ, ING4-deletion cell line, cell migration assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor colocalization plus pharmacological epistasis, single lab\",\n      \"pmids\": [\"34871062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CK2 (casein kinase 2) phosphorylates ING4 at Ser-150, triggering ING4 ubiquitination and degradation by the JFK E3 ubiquitin ligase. CK2 knockout increases ING4 protein stability and enhances T cell anti-tumor activity by allowing ING4-dependent PD-L1 autophagic degradation, thereby suppressing NSCLC immune escape.\",\n      \"method\": \"CK2 knockout, phospho-site mapping (ING4-S150), ubiquitination assay, protein stability assay, PD-L1 expression/autophagic degradation assay, T cell co-culture assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site identification plus ubiquitination assay plus functional immune escape readout, single lab\",\n      \"pmids\": [\"37870169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ING4 and ING5 are essential components of the KAT6A/KAT6B/KAT7 HAT complexes required for histone H3K14 acetylation and H3K23 acetylation; Ing4/Ing5 double-knockout embryos show loss of H3K14ac and reduced H3K23ac. ING4/ING5 are required for epicardial cell lineage development and proepicardium outgrowth, with Ing4+/−Ing5−/− hearts showing epicardial and coronary vasculature defects.\",\n      \"method\": \"Mouse knockout genetics, histone modification Western blot/ChIP, cardiac phenotype analysis, cell adhesion gene expression\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with direct histone modification measurement and defined developmental phenotype, multiple genotypes tested\",\n      \"pmids\": [\"38446206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ing4 deficiency in hematopoietic stem cells (HSCs) promotes a transcriptionally poised state with gene expression signatures of activation yet G0 arrest; Ing4-deficient HSCs show enhanced regenerative capacity after transplantation, indicating ING4 regulates HSC quiescence and self-renewal balance.\",\n      \"method\": \"Mouse Ing4 knockout, transcriptome analysis, cell cycle analysis (G0 markers), competitive transplantation assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with transcriptomics and functional transplantation readout, single lab\",\n      \"pmids\": [\"39175773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A cancer-associated ING4 mutant (N214D) found in human tumors shows dramatically reduced ability to inhibit proliferation, anchorage-independent growth, and cell migration, and sensitize to cell death; the functional impairment correlates with reduced protein stability due to increased proteasome-mediated degradation, not with altered H3K4me3 binding or folding.\",\n      \"method\": \"Mutagenesis, protein stability assay, proteasome inhibitor rescue, proliferation/migration/soft agar assays, histone binding assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis with multiple orthogonal functional and biochemical assays, single lab\",\n      \"pmids\": [\"20705953\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ING4 is a tumor suppressor that functions as a native subunit of the HBO1/KAT7 histone acetyltransferase complex, where its PHD finger reads the H3K4me3 chromatin mark to recruit the complex to target promoters and drive H3 acetylation; it forms homodimers via an N-terminal coiled-coil domain enabling bivalent H3K4me3 recognition, interacts with p53 (via its NLS region) to enhance p53 acetylation and transcriptional activity, directly binds and represses NF-κB (p65/RelA) at target promoters by modulating histone acetylation and HDAC-1 recruitment, associates with HIF prolyl hydroxylases to repress HIF transcriptional activity, inhibits MYC translation by associating with AUF1, and promotes rRNA transcription in the nucleolus; its protein stability is regulated by CK2-mediated phosphorylation at Ser-150 followed by SCF(JFK)-mediated ubiquitination and proteasomal degradation, and its activity can be further modulated by PAD4-mediated citrullination of the NLS, which disrupts p53 binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ING4 is a chromatin-reading tumor suppressor that couples recognition of the H3K4me3 active-promoter mark to histone acetyltransferase activity and to the control of multiple transcriptional programs governing growth, apoptosis, angiogenesis, and differentiation [#12, #5]. It functions as a native subunit of the HBO1 (KAT7) histone acetyltransferase complex, where its PHD finger specifically binds H3K4me3 to augment HBO1-driven H3 acetylation at target promoters, an interaction required for ING4-dependent apoptosis after genotoxic stress and for suppression of anchorage-independent growth [#12]; ING4 and the paralog ING5 are similarly essential for H3K14 and H3K23 acetylation by KAT6A/KAT6B/KAT7 complexes during epicardial lineage development [#29]. ING4 homodimerizes through an N-terminal antiparallel coiled-coil, presenting two independent H3K4me3-binding PHD fingers for bivalent chromatin recognition, and disruption of dimerization abolishes its pro-apoptotic activity [#13, #16]. Beyond the acetyltransferase complex, ING4 enhances p53 acetylation and p53-dependent p21 induction and apoptosis through an interaction requiring its NLS region [#0, #4], and directly binds NF-\\u03baB p65/RelA to repress NF-\\u03baB target genes at the chromatin level by lowering p300 recruitment, histone acetylation and H3K4me3 while promoting HDAC-1 recruitment, thereby restraining tumor angiogenesis [#1, #9]. It additionally represses HIF transcriptional activity via association with HIF prolyl hydroxylases independently of HIF stability [#3, #7], represses MYC at the translational level by binding AUF1 on MYC mRNA [#18], and drives rRNA transcription in the nucleolus through PHD-dependent localization to active rDNA promoters [#25]. ING4 abundance is controlled by CK2-mediated phosphorylation at Ser-150 that licenses SCF(JFK)-mediated ubiquitination and proteasomal degradation [#22, #28], and its p53-activating function is further modulated by PAD4-mediated citrullination of the NLS, which disrupts p53 binding [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established ING4 as a p53 cofactor, answering whether it acts through a defined transcriptional partner to enforce growth arrest and apoptosis.\",\n      \"evidence\": \"Co-IP with p300 and p53, p21/WAF1 reporter, and apoptosis/colony assays\",\n      \"pmids\": [\"12750254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the ING4 region required for p53 binding\", \"Did not establish whether p53 enhancement occurs within a HAT complex\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified NF-\\u03baB p65/RelA as a second direct target and linked ING4 to suppression of tumor angiogenesis, broadening its role beyond p53.\",\n      \"evidence\": \"Co-IP with p65, gene expression analysis, and brain tumor xenograft\",\n      \"pmids\": [\"15029197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-level mechanism of repression not yet defined\", \"Relationship to the p53 pathway unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the NLS region as the p53-binding determinant and showed ING4 represses HIF transcriptional activity via prolyl hydroxylase association, expanding its target repertoire to the hypoxic response.\",\n      \"evidence\": \"GST pulldown and NLS mutagenesis for p53; Co-IP with PHD/HPH and HIF reporter with stability controls\",\n      \"pmids\": [\"15882981\", \"15897452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab NLS mapping\", \"Did not resolve whether HIF repression is direct or chromatin-mediated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the structural basis for chromatin reading by ING4, answering how it is targeted to active promoters and distinguishing it from the phosphoinositide-binding ING2.\",\n      \"evidence\": \"NMR structure of the PHD finger with methylated histone and phosphoinositide binding assays\",\n      \"pmids\": [\"17157298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect H3K4me3 reading to a specific enzymatic complex\", \"Functional consequence of reading not yet shown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved how ING4 represses NF-\\u03baB without blocking its activation: it remodels the chromatin environment at target promoters rather than preventing p65 DNA binding.\",\n      \"evidence\": \"ChIP, Co-IP, and siRNA showing reduced p300/acetyl-histone/H3K4me3 and increased HDAC-1 at promoters\",\n      \"pmids\": [\"18779315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the acetyltransferase complex delivering ING4 to these promoters\", \"Splice-variant and localization control addressed separately\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Unified the chromatin-reading and acetylation activities by showing ING4 is a native HBO1 HAT subunit whose PHD-H3K4me3 engagement augments H3 acetylation and is required for genotoxic apoptosis.\",\n      \"evidence\": \"Co-IP, in vitro HAT reconstitution, ChIP, PHD mutagenesis, and anchorage-independent growth assay\",\n      \"pmids\": [\"19187765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of ING4 within the complex not defined\", \"Did not address dimerization\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the oligomeric architecture of ING4, showing an antiparallel coiled-coil homodimer that presents two PHD fingers for bivalent recognition and is functionally required for apoptosis.\",\n      \"evidence\": \"NMR of full-length protein, analytical ultracentrifugation, crystal structure of the dimerization domain, and dimerization mutant apoptosis assays\",\n      \"pmids\": [\"20053357\", \"22334692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show bivalent engagement on nucleosomal arrays\", \"Link between dimerization and HBO1 targeting inferred, not directly measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended ING4 mechanism to post-transcriptional and paracrine control, showing translational MYC repression via AUF1 and an H3K4me3/p53-dependent fibroblast secretory phenotype affecting tumor growth.\",\n      \"evidence\": \"Co-IP and mRNP-IP with AUF1 on MYC mRNA; PHD-mutant and p53-dependency assays with co-injection xenografts\",\n      \"pmids\": [\"23603392\", \"23604125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AUF1-MYC mechanism not reconstituted\", \"Paracrine secretory program direction (tumor-promoting vs suppressing) context-dependent\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the degradation machinery for ING4, showing SCF(JFK) ubiquitinates and destabilizes it and that this destabilization hyperactivates NF-\\u03baB to drive metastasis.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, stability assays, and in vivo metastasis model\",\n      \"pmids\": [\"25792601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal triggering JFK targeting not defined here\", \"Degradation site not yet mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected ING4 chromatin function to ribosome biogenesis, showing PHD-dependent nucleolar localization at active rDNA promotes H3K9ac, UBF occupancy, and rRNA transcription.\",\n      \"evidence\": \"Immunofluorescence, CRISPR/RNAi deficiency, ChIP for H3K9ac/UBF, and rescue by re-expression\",\n      \"pmids\": [\"31754246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HBO1/KAT complex mediates rDNA acetylation not shown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established physiological developmental and stem-cell roles, showing ING4/ING5 are required for KAT6/KAT7-dependent H3K14/H3K23 acetylation in cardiac development and that ING4 regulates HSC quiescence and self-renewal.\",\n      \"evidence\": \"Mouse Ing4/Ing5 knockout genetics with histone modification ChIP/Western, cardiac phenotyping, HSC transcriptomics and competitive transplantation\",\n      \"pmids\": [\"38446206\", \"39175773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vivo target promoters of ING4 in these tissues not catalogued\", \"Mechanism linking ING4 loss to the HSC poised state undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the kinase signal upstream of ING4 degradation and a new functional consequence, showing CK2 phosphorylation at Ser-150 licenses JFK-mediated degradation and that stabilized ING4 promotes PD-L1 autophagic clearance to limit immune escape.\",\n      \"evidence\": \"CK2 knockout, phospho-site mapping, ubiquitination/stability assays, PD-L1 degradation and T-cell co-culture assays\",\n      \"pmids\": [\"37870169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ING4 to PD-L1 autophagy not molecularly defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ING4's distinct activities — HBO1/KAT-complex acetylation, p53 cofactor function, NF-\\u03baB repression, and nucleolar rRNA control — are coordinated and prioritized in a given cell state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide map distinguishing direct ING4-HBO1 targets from p53/NF-\\u03baB-dependent ones\", \"Quantitative partitioning of ING4 among its protein partners unknown\", \"No human Mendelian disease link established in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5, 12, 13, 25]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 9, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [11, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 9, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 9, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 12, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [22, 28, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [29, 21, 30]}\n    ],\n    \"complexes\": [\n      \"HBO1/KAT7 histone acetyltransferase complex\",\n      \"KAT6A/KAT6B/KAT7 HAT complex\",\n      \"SCF(JFK) E3 ubiquitin ligase complex\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"RELA\",\n      \"EP300\",\n      \"EGLN1\",\n      \"AUF1\",\n      \"SIRT1\",\n      \"KAT7\",\n      \"JFK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}