{"gene":"ING1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1996,"finding":"ING1 (p33ING1) was identified as a nuclear growth inhibitor whose acute overexpression inhibits cell growth and whose chronic antisense suppression promotes neoplastic transformation, establishing it as a candidate tumor suppressor.","method":"Subtractive hybridization/GSE cloning; transfection overexpression and antisense chronic expression assays in cell lines","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (antisense) and gain-of-function (overexpression) in multiple cell systems, single lab but two orthogonal functional readouts","pmids":["8944021"],"is_preprint":false},{"year":1997,"finding":"p33ING1 protein localizes to the nucleus, consistent with its role as a growth regulator.","method":"Indirect immunofluorescence; fluorescence in situ hybridization for chromosomal localization","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence, replicated in subsequent studies","pmids":["9186514"],"is_preprint":false},{"year":1997,"finding":"ING1 RNA and protein levels are 8–10-fold higher in senescent human diploid fibroblasts than in young cells; chronic antisense ING1 expression extends the proliferative lifespan by ~7 population doublings, establishing ING1 as a regulator of cellular senescence.","method":"Quantitative RT-PCR/Western blot; antisense chronic expression with proliferative lifespan measurement","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and expression quantification, single lab","pmids":["9121449"],"is_preprint":false},{"year":1997,"finding":"p33ING1 promotes apoptosis: its levels increase upon apoptosis induction, overexpression enhances serum starvation-induced apoptosis synergistically with Myc, and antisense ING1 protects cells from apoptosis.","method":"Tetracycline-controlled c-myc system; antisense ING1 stable expression; apoptosis assays in P19 and fibroblast cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with apoptosis readout in multiple cell types, single lab","pmids":["9102209"],"is_preprint":false},{"year":1998,"finding":"p33ING1 physically associates with p53 by co-immunoprecipitation, and the biological growth-inhibitory effects of ING1 require active p53; ING1 cooperates with p53 to activate transcription from the p21/WAF1 promoter.","method":"Co-immunoprecipitation; p21/WAF1 promoter-luciferase reporter assays; antisense/dominant-negative suppression epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional epistasis plus physical interaction by Co-IP, replicated across multiple subsequent studies","pmids":["9440695"],"is_preprint":false},{"year":1999,"finding":"The longer mouse ing1 isoform (p47 equivalent) forms a detectable complex with p53 by immunoprecipitation and interferes with p53 protein accumulation and p53-responsive promoter activation after DNA damage, while the shorter isoform (p33 equivalent) activates p53 responses — demonstrating that a single locus encodes both p53-suppressing and p53-activating proteins.","method":"Co-immunoprecipitation; p53-responsive promoter-reporter assays; Western blot after DNA damage","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter assays, single lab, mouse ortholog","pmids":["10542254"],"is_preprint":false},{"year":2000,"finding":"Three yeast ING1 homologs (Yng1, Yng2, Pho23) co-immunoprecipitate with histone acetyltransferase (HAT) activity; Yng2 interacts with Tra1 (a NuA4 HAT complex component) by yeast two-hybrid and Co-IP, linking ING1-family proteins to HAT complexes and chromatin remodeling.","method":"Yeast two-hybrid; co-immunoprecipitation; HAT activity assays; yeast genetics (deletion phenotypes rescued by human ING1)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, Co-IP, in vitro HAT assay, genetic rescue), replicated for multiple homologs","pmids":["10805724"],"is_preprint":false},{"year":2000,"finding":"p33ING1b (but not p24ING1c) associates with the mSin3 transcriptional corepressor complex including Sin3, SAP30, HDAC1, and RbAp48; ING1 immune complexes deacetylate core histones in vitro; p33ING1b is functionally associated with HDAC1-mediated transcriptional repression.","method":"Co-immunoprecipitation; in vitro histone deacetylase assay; transcriptional repression reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical complex isolation, in vitro enzymatic assay, and functional reporter assay; replicated by independent lab (Kuzmichev 2002)","pmids":["11118440"],"is_preprint":false},{"year":2001,"finding":"UV irradiation rapidly induces p33ING1b to bind PCNA through a PCNA-interacting protein (PIP) domain; PIP mutants that cannot bind PCNA fail to induce apoptosis and instead protect cells from UV-induced apoptosis, establishing that ING1-PCNA interaction is required for UV-induced programmed cell death.","method":"Co-immunoprecipitation; PIP domain mutagenesis; apoptosis assays after UV; competitive inhibition by p21 overexpression","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mutagenesis with defined functional readout (apoptosis), competitive inhibition control, multiple orthogonal methods","pmids":["11682605"],"is_preprint":false},{"year":2001,"finding":"UV irradiation induces nucleolar translocation of ING1 proteins; ING1 contains two distinct 4-amino-acid nucleolar targeting sequences (NTS); NTS mutants that fail to translocate to the nucleolus do not efficiently induce apoptosis and instead protect cells from UV-induced apoptosis.","method":"Live-cell imaging with GFP fusions; NTS deletion/point mutants; apoptosis assays; fluorescence microscopy","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by live imaging with functional consequence established by mutagenesis, replicated by multiple independent studies","pmids":["11353074"],"is_preprint":false},{"year":2001,"finding":"p33ING1b (ING1) enhances repair of UV-damaged DNA and physically interacts with GADD45; this DNA repair function requires p53.","method":"Host-cell-reactivation DNA repair assay; co-immunoprecipitation of ING1 and GADD45; overexpression/antisense experiments","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional repair assay plus Co-IP interaction, single lab","pmids":["11431327"],"is_preprint":false},{"year":2001,"finding":"Yng2p (yeast ING1 homolog) is a stable stoichiometric subunit of the NuA4 HAT complex; NuA4 from Δyng2 cells shows weak HAT activity; Yng2 PHD finger is required for full expression of p53-responsive genes and targeted NuA4-dependent histone H4 hyperacetylation.","method":"Mass spectrometry; immunoblotting; immunoprecipitation of purified NuA4; in vitro p53 interaction; histone acetylation assays in yeast","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of complex by MS + Co-IP, in vitro HAT assay, genetic deletion phenotype, multiple orthogonal methods","pmids":["11604499"],"is_preprint":false},{"year":2002,"finding":"p33ING1b, but not p47ING1a, interacts with HAT-associated proteins (TRRAP, PCAF, CBP, p300) and induces hyperacetylation of histones H3 and H4 in vitro and in vivo; p47ING1a inhibits histone acetylation and binds HDAC1; p33ING1b affects the PCNA-p300 physical association.","method":"Co-immunoprecipitation; in vitro HAT assays; in vivo single-cell histone acetylation imaging; Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, in vitro enzymatic assay, in vivo imaging), isoform-specific effects established","pmids":["12015309"],"is_preprint":false},{"year":2002,"finding":"p33ING1b associates with the Sin3-HDAC complex through direct interaction between its N-terminal domain and SAP30; two distinct Sin3-p33ING1b complexes exist, one of which additionally contains Brg1-based SWI/SNF subunits; growth suppression by p33ING1b requires the intact Sin3-HDAC-interacting domain.","method":"Co-immunoprecipitation; biochemical complex purification; domain deletion/interaction mapping; growth suppression assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical complex purification, domain mapping of direct interaction, functional domain requirement established","pmids":["11784859"],"is_preprint":false},{"year":2003,"finding":"p33ING1b represses AFP promoter transcription by binding AT-motifs and excluding HNF1, and also by physically interacting with hSIR2 (SIRT1) to inhibit its deacetylase activity, thereby increasing acetylation of p53 at Lys373/382 and enhancing p53-dependent transcription.","method":"Electrophoretic mobility shift assay (EMSA); promoter-reporter assays; co-immunoprecipitation; p53 acetylation Western blot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus EMSA plus functional reporter assays, single lab","pmids":["14522900"],"is_preprint":false},{"year":2005,"finding":"p33ING1b contains two autonomous transcriptional silencing domains: an N-terminal domain whose silencing is HDAC-dependent (sensitive to TSA) and a C-terminal domain whose silencing is HDAC-independent (TSA-resistant); oncogenic Ras enhances ING1-mediated silencing through the MAP kinase pathway.","method":"Transcriptional reporter assays with deletion mutants; TSA and MAP kinase inhibitor treatment; colony formation assays; thymidine incorporation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with functional readout, pharmacological pathway dissection, single lab","pmids":["15601862"],"is_preprint":false},{"year":2006,"finding":"p33ING1b interacts with 14-3-3 family proteins in a phosphorylation-dependent manner, causing significant cytoplasmic tethering of ING1b; overexpression of 14-3-3 inhibits ING1b-mediated induction of p21WAF1 after UV damage, demonstrating that subcellular mislocalization blocks ING1 biological activity.","method":"Co-immunoprecipitation; phosphatase treatment; subcellular fractionation; p21WAF1 Western blot; bioinformatics NLS/14-3-3 motif analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with phosphorylation dependency, fractionation, functional p21 readout, single lab","pmids":["16581770"],"is_preprint":false},{"year":2006,"finding":"ARF physically interacts with p33ING1 in vivo, displaces ING1 from nuclear to nucleolar localization, and ARF-deficient primary fibroblasts show impaired ING1-mediated cell cycle arrest and p21CIP1/Mdm2 induction.","method":"Co-immunoprecipitation in vivo; fluorescence microscopy; ARF knockout MEFs; cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus localization plus genetic loss-of-function epistasis, single lab","pmids":["16607280"],"is_preprint":false},{"year":2007,"finding":"Phosphorylation of p33ING1b at Ser-126 stabilizes the protein; Chk1 phosphorylates Ser-126 predominantly upon DNA damage while Cdk1 does so under basal conditions; mutation of Ser-126 to Ala dramatically shortens ING1b half-life and alters cyclin B1 expression and melanoma cell proliferation.","method":"In vitro kinase assays with Chk1 and Cdk1; pulse-chase/half-life measurement; Ser126Ala mutagenesis; cyclin B1 Western blot; proliferation assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis with protein stability and functional readouts, single lab but multiple methods","pmids":["17585055"],"is_preprint":false},{"year":2007,"finding":"Ing1-deficient mouse embryonic fibroblasts show defective senescence-like antiproliferative response to oncogenic Ras, reduced p53 protein stability, and impaired heterochromatin formation during oncogene-induced senescence.","method":"Ing1 knockout MEFs; oncogenic Ras expression; p53 stability assays; heterochromatin mark immunostaining; senescence assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple phenotypic readouts, single lab","pmids":["17693408"],"is_preprint":false},{"year":2007,"finding":"p37Ing1 (mouse ING1) suppresses cell proliferation in a p53-independent manner; loss of p37Ing1 induces Bax expression and increases DNA damage-induced apoptosis irrespective of p53 status; p37Ing1 suppresses spontaneous follicular B-cell lymphomas in mice.","method":"p37Ing1 knockout mice; proliferation assays in p53 wild-type and p53-null backgrounds; Bax Western blot; tumor incidence monitoring","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout in defined p53-null background establishes p53-independence, multiple phenotypic readouts, single lab","pmids":["17332334"],"is_preprint":false},{"year":2008,"finding":"The ING1 PHD finger binds histone H3 trimethylated at Lys4 (H3K4me3) but not other histone modifications; a 2.1 Å crystal structure reveals that Y212 and W235 form a hydrophobic pocket making cation-π contacts with the trimethylammonium group; W235A and cancer-associated mutations (N216S, V218I, G221V) disrupt H3K4me3 binding and abolish ING1's ability to stimulate DNA repair and promote apoptosis.","method":"Peptide microarray; X-ray crystallography (2.1 Å); site-directed mutagenesis; UV-induced DNA repair assay (host-cell reactivation); apoptosis assays in stable melanoma cell clones","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation plus functional rescue experiments; multiple orthogonal methods in one rigorous study","pmids":["18533182"],"is_preprint":false},{"year":2008,"finding":"ING1 proteins contain a lamin interaction domain (LID) through which they bind and colocalize with lamin A; LMNA-/- cells show reduced ING1 levels and ING1 mislocalization; ectopic lamin A re-targets ING1 to the nucleus; ING1 lacking the LID does not interact with lamin A and cannot affect apoptosis.","method":"Co-immunoprecipitation; lamin A knockout cells; ectopic lamin A expression; GFP-ING1 localization imaging; LID deletion mutagenesis; apoptosis assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, genetic knockout, domain mutagenesis, and functional apoptosis readout; multiple orthogonal methods","pmids":["18836436"],"is_preprint":false},{"year":2008,"finding":"p33ING1b interacts with nuclear import machinery (karyopherins alpha2 and beta1) through basic NLS sequences adjacent to its PHD domain; deletion of NLS motifs prevents complete nuclear localization and abolishes ING1b-induced p21WAF1 expression.","method":"Co-immunoprecipitation; NLS deletion mutagenesis; subcellular localization imaging; p21WAF1 Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis with functional readout, single lab","pmids":["18655775"],"is_preprint":false},{"year":2008,"finding":"p33ING1b is degraded by the 20S proteasome; NQO1 inhibits its proteasomal degradation; UV irradiation induces phosphorylation at Ser-126, which facilitates ING1b interaction with NQO1 and thereby stabilizes the protein.","method":"Proteasome inhibitors; partial proteasome complex isolation; in vitro degradation assays; in vitro interaction assays; NQO1 co-immunoprecipitation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro degradation reconstitution, complex isolation, and interaction assays; multiple complementary biochemical methods","pmids":["18388957"],"is_preprint":false},{"year":2010,"finding":"ING1 binds to the DGCR8 promoter and represses its transcription through chromatin regulation; ING1 and DGCR8 cooperate to restrain cell proliferation.","method":"Genome-wide expression microarray in Ing1-null MEFs; chromatin immunoprecipitation (ChIP) at DGCR8 promoter; proliferation assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional proliferation assay, genome-wide expression context, single lab","pmids":["20179197"],"is_preprint":false},{"year":2010,"finding":"p33ING1b triggers cellular senescence in a p53-dependent manner in human primary fibroblasts; endogenous ING1 accumulates in chromatin in oncogene-induced senescent cells; recognition of H3K4me3 by the PHD finger is required for ING1-induced senescence; a tumor-derived ING1 mutant fails to induce senescence.","method":"RNAi knockdown; PHD-finger point mutants; oncogene-induced senescence assays; chromatin fractionation; gene expression profiling","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with functional senescence readout plus chromatin fractionation, single lab","pmids":["21078114"],"is_preprint":false},{"year":2011,"finding":"ING1 stabilizes wild-type p53 by blocking its polyubiquitination; ING1 contains a ubiquitin-binding domain (UBD) overlapping its polybasic region (PBR) that binds ubiquitin with high affinity (Kd ~100 nM); ING1 physically interacts with the deubiquitinase HAUSP; knockdown of HAUSP blocks ING1-mediated p53 stabilization.","method":"Ubiquitin-binding assays; co-immunoprecipitation of ING1-HAUSP; p53 ubiquitination Western blots; ING1 knockdown; affinity binding measurements","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, biochemical binding assay with Kd measurement, and genetic knockdown with functional readout; single lab","pmids":["21731648"],"is_preprint":false},{"year":2011,"finding":"p33ING1b upregulates p16INK4a transcription to induce cellular senescence; p33ING1b and the HAT p300 bind to the p16INK4a promoter; the p300/CBP inhibitor curcumin reverses p16INK4a induction by p33ING1b.","method":"Overexpression; RT-PCR/Western blot for p16; chromatin immunoprecipitation (ChIP); pharmacological inhibition","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and pharmacological inhibition with functional readout, single lab","pmids":["21896275"],"is_preprint":false},{"year":2012,"finding":"After UV irradiation, p33ING1 translocates into the nucleolus and binds the nucleolar protein CSIG; this interaction requires ING1's nucleolar targeting sequence; ING1 enhances CSIG protein stability; the ING1-CSIG complex promotes apoptosis via Bax activation.","method":"Co-immunoprecipitation; fluorescence microscopy; UV irradiation; Western blot for CSIG stability; apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus localization plus functional apoptosis readout, single lab","pmids":["22419112"],"is_preprint":false},{"year":2013,"finding":"ING1 (Ing1) is required for targeting active DNA demethylation by recruiting the DNA demethylation regulator Gadd45a to H3K4me3-marked chromatin; reduced H3K4 methylation impairs Gadd45a/Ing1 recruitment and gene-specific DNA demethylation.","method":"Xenopus laevis model; Ing1 knockdown; Gadd45a recruitment assays; DNA methylation analysis; H3K4me3 ChIP","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with DNA methylation readout and ChIP in Xenopus, single lab","pmids":["23388825"],"is_preprint":false},{"year":2013,"finding":"ING1 translocates to the mitochondria in response to apoptosis-inducing stimuli independently of p53; endogenous ING1 physically interacts with BAX and colocalizes with BAX upon UV in a UV-inducible manner; mitochondria-targeted ING1 induces apoptosis more efficiently than wild-type ING1; ING1 contains a BH3-like domain.","method":"Subcellular fractionation; co-immunoprecipitation of ING1 and BAX; mitochondria-targeted ING1 construct; apoptosis assays in multiple breast cancer cell lines; immunofluorescence colocalization","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus fractionation plus targeted construct functional comparison; single lab, multiple cell lines","pmids":["24008732"],"is_preprint":false},{"year":2013,"finding":"Src tyrosine kinase physically associates with and phosphorylates ING1 both in vitro and in vivo, causing nuclear-to-cytoplasmic relocalization and decreased ING1 stability; Src antagonizes ING1-induced apoptosis through both kinase-dependent and kinase-independent mechanisms.","method":"In vitro kinase assay; co-immunoprecipitation; subcellular localization imaging; apoptosis assays; kinase-dead Src controls","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus Co-IP plus functional apoptosis readout, single lab","pmids":["23585863"],"is_preprint":false},{"year":2017,"finding":"ING1b binds rDNA chromatin, recruits HDAC1 to rDNA loci, increases association of rDNA with the NoRC repressor complex, deacetylates active histone marks H3K9 and H3K27 on rDNA, and thereby represses rRNA/rDNA transcription; loss of ING1 enhances nucleolar localization of phospho-mTOR and its association with Raptor and GβL; ING1 inhibits UBF activity and the UBF-mTOR interaction.","method":"ChIP of ING1, HDAC1, NoRC, H3K9ac, H3K27ac at rDNA; co-immunoprecipitation; rRNA quantification; mTOR localization imaging; knockdown experiments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus rRNA functional readout, single lab, multiple orthogonal methods","pmids":["27903908"],"is_preprint":false},{"year":2002,"finding":"Mouse ING1 homolog (mINGh) physically interacts with the anti-apoptotic protein A1/Bfl-1 (identified by yeast two-hybrid); mINGh enhances cell death in mammary epithelial cells and this effect is inhibited by A1, placing ING1 in a functional antagonism with A1 in apoptosis regulation.","method":"Yeast two-hybrid screen; apoptosis assays in HC11 mammary epithelial cells; A1 overexpression co-transfection","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid interaction with functional co-expression assay, single lab, no confirmatory Co-IP in mammalian cells reported in abstract","pmids":["11888890"],"is_preprint":false},{"year":2005,"finding":"The PCNA-associated protein p15PAF interacts with p33ING1b in the same complex in cell cultures; this interaction is detected by co-immunoprecipitation and both proteins show UV-enhanced association.","method":"Co-immunoprecipitation; immunofluorescence colocalization","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, no mechanistic follow-up in abstract","pmids":["16288740"],"is_preprint":false},{"year":2003,"finding":"p33ING1b weakly physically associates with estrogen receptor alpha (ERα) in vitro and enhances estrogen-induced ERα transcriptional activity through the AF2 domain of ERα, acting as a coactivator.","method":"In vitro translated protein interaction assay; ERα transcriptional reporter assays; AF2 deletion mutant analysis","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro pull-down and reporter assay only, weak interaction noted, single lab","pmids":["14630091"],"is_preprint":false},{"year":2021,"finding":"ING1 and ING2 are recruited to a negative androgen response element (nARE) in the hTERT promoter in an androgen-dependent manner and mediate AR-regulated transcriptional repression of hTERT; ING1 and ING2 knockdown impairs this repression.","method":"Chromatin immunoprecipitation (ChIP); promoter-reporter assays; siRNA knockdown; ex vivo patient samples","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown with reporter assay plus ex vivo validation, single lab","pmids":["34439179"],"is_preprint":false}],"current_model":"ING1 (primarily the p33ING1b isoform) is a nuclear tumor suppressor that functions as an epigenetic 'reader' by binding H3K4me3 through its PHD finger domain, thereby targeting histone acetyltransferase (HAT; e.g., NuA4/TRRAP/p300/CBP) and histone deacetylase (HDAC; Sin3-HDAC1 via SAP30) complexes to chromatin to regulate transcription, DNA repair, and apoptosis; it physically associates with and cooperates with p53 to activate p21WAF1 and promote growth arrest, stabilizes p53 by recruiting the deubiquitinase HAUSP to block polyubiquitination, binds PCNA through a PIP domain upon UV damage to promote apoptosis, is targeted to the nucleus by lamin A (via a lamin interaction domain) and by karyopherins, is regulated by phosphorylation (Chk1/Cdk1 at Ser-126) that stabilizes it via NQO1 and modulates 14-3-3-dependent cytoplasmic sequestration, translocates to mitochondria to interact with BAX and promote p53-independent apoptosis, and recruits HDAC1 to rDNA to repress rRNA transcription."},"narrative":{"mechanistic_narrative":"ING1 is a nuclear tumor suppressor that couples epigenetic chromatin reading to the control of proliferation, senescence, DNA repair, and apoptosis [PMID:8944021, PMID:9121449, PMID:18533182]. Its PHD finger is a sequence-specific reader of histone H3 trimethylated at Lys4 (H3K4me3): a 2.1 Å structure shows Y212 and W235 forming a hydrophobic pocket that engages the trimethylammonium group through cation-π contacts, and cancer-associated PHD mutations abolish H3K4me3 binding and disable ING1's ability to stimulate DNA repair and promote apoptosis [PMID:18533182]. Through this reader function ING1 docks chromatin-modifying machinery, partitioning between activating histone acetyltransferase complexes (NuA4/Tra1, TRRAP/PCAF/CBP/p300), which it uses to drive H3/H4 hyperacetylation in an isoform-specific manner, and repressive Sin3-HDAC1 complexes, which the p33ING1b N-terminus engages directly via SAP30 to silence transcription [PMID:10805724, PMID:11604499, PMID:12015309, PMID:11784859]. ING1 acts largely in concert with p53: it physically associates with p53, cooperates to transactivate p21WAF1 and drive growth arrest, stabilizes wild-type p53 by binding ubiquitin through a UBD and recruiting the deubiquitinase HAUSP to block polyubiquitination, and is required for oncogene-induced senescence and p53-dependent heterochromatin formation [PMID:9440695, PMID:17693408, PMID:21078114, PMID:21731648]. The shorter and longer ING1 isoforms have opposing effects on p53, so a single locus encodes both p53-activating and p53-suppressing proteins [PMID:10542254]. ING1 also operates p53-independently, suppressing proliferation, inducing Bax, and translocating to mitochondria where, via a BH3-like domain, it interacts with BAX to promote apoptosis [PMID:17332334, PMID:24008732]. ING1 activity is gated by localization and stability: it requires a lamin-A interaction domain and karyopherin-dependent nuclear import, undergoes UV-induced nucleolar translocation to bind PCNA (via a PIP domain) and CSIG to commit cells to apoptosis, and is regulated by phosphorylation at Ser-126 (by Chk1 and Cdk1) that stabilizes it through NQO1, while 14-3-3 binding and Src-mediated phosphorylation drive cytoplasmic sequestration that blocks its function [PMID:11682605, PMID:11353074, PMID:16581770, PMID:17585055, PMID:18836436, PMID:18655775, PMID:18388957, PMID:22419112, PMID:23585863]. At the nucleolus ING1b recruits HDAC1 and the NoRC complex to rDNA to deacetylate active marks and repress rRNA transcription [PMID:27903908].","teleology":[{"year":1996,"claim":"Established ING1 as a candidate tumor suppressor by showing its expression bidirectionally controls cell growth, addressing whether the gene actively restrains proliferation.","evidence":"Subtractive/GSE cloning with overexpression and chronic antisense in cell lines","pmids":["8944021"],"confidence":"Medium","gaps":["No molecular mechanism for growth inhibition","Single lab functional readouts","No in vivo tumor data"]},{"year":1997,"claim":"Linked ING1 to senescence and apoptosis, defining the cellular programs it engages beyond simple growth inhibition.","evidence":"Immunofluorescence localization, expression quantification in senescent fibroblasts, and antisense/overexpression apoptosis assays","pmids":["9186514","9121449","9102209"],"confidence":"Medium","gaps":["No molecular effectors identified","Mechanism of senescence/apoptosis induction unknown"]},{"year":1998,"claim":"Showed ING1 physically and functionally cooperates with p53 to activate p21WAF1, placing it within the p53 growth-arrest pathway.","evidence":"Co-IP, p21/WAF1 promoter-reporter assays, and antisense/dominant-negative epistasis","pmids":["9440695"],"confidence":"High","gaps":["Direct vs indirect p53 binding not resolved","Did not address p53-independent functions"]},{"year":1999,"claim":"Revealed that the ING1 locus encodes isoforms with opposing effects on p53, explaining functional heterogeneity within the gene.","evidence":"Co-IP and p53-responsive reporter assays after DNA damage with mouse isoforms","pmids":["10542254"],"confidence":"Medium","gaps":["Mechanistic basis of opposing isoform activity unclear","Mouse ortholog only"]},{"year":2000,"claim":"Connected ING1-family proteins to histone acetyltransferase and Sin3-HDAC corepressor complexes, defining ING1 as a chromatin-modifying complex component.","evidence":"Yeast two-hybrid, Co-IP, HAT activity assays, genetic rescue, in vitro HDAC assays, and reporter assays","pmids":["10805724","11118440"],"confidence":"High","gaps":["How ING1 selects HAT vs HDAC complexes not defined","Chromatin targeting determinant unknown"]},{"year":2001,"claim":"Established the DNA-damage response axis of ING1, linking UV-induced PCNA binding and nucleolar targeting to commitment to apoptosis and DNA repair.","evidence":"PIP and NTS domain mutagenesis with apoptosis assays, host-cell reactivation repair assays, GADD45 Co-IP, and NuA4 reconstitution by MS in yeast","pmids":["11682605","11353074","11431327","11604499"],"confidence":"High","gaps":["How PCNA binding switches repair to apoptosis unresolved","Nucleolar effectors not yet identified"]},{"year":2002,"claim":"Mapped isoform-specific partitioning between acetylation-promoting and deacetylation-promoting complexes via direct SAP30 binding, defining how ING1 imposes activating or repressive chromatin states.","evidence":"Co-IP, in vitro HAT assays, in vivo acetylation imaging, complex purification, and domain-mapping growth suppression assays","pmids":["12015309","11784859"],"confidence":"High","gaps":["Structural basis of complex selection not defined","Determinants directing isoform-specific partner choice unclear"]},{"year":2003,"claim":"Extended ING1's reach to SIRT1 inhibition and promoter-specific DNA binding, showing it tunes p53 acetylation and represses target promoters.","evidence":"EMSA, promoter-reporter assays, Co-IP, and p53 acetylation Western blots","pmids":["14522900"],"confidence":"Medium","gaps":["Direct SIRT1 inhibition mechanism not structurally defined","Single lab"]},{"year":2005,"claim":"Defined two autonomous silencing domains with distinct HDAC dependence and showed oncogenic Ras enhances ING1 silencing, integrating signaling input into its repressive function.","evidence":"Deletion-mutant reporter assays with TSA and MAPK inhibitor treatment plus colony formation","pmids":["15601862"],"confidence":"Medium","gaps":["Mechanism of HDAC-independent C-terminal silencing unknown","Direct Ras/MAPK target on ING1 not identified"]},{"year":2006,"claim":"Showed ING1 is subject to spatial and signaling regulation through ARF-driven nucleolar redistribution and phospho-dependent 14-3-3 cytoplasmic tethering that blocks its activity.","evidence":"Co-IP, phosphatase treatment, subcellular fractionation, ARF-knockout MEFs, and p21WAF1 readouts","pmids":["16581770","16607280"],"confidence":"Medium","gaps":["Kinase generating the 14-3-3 site not defined here","Functional relationship of ARF and 14-3-3 control unresolved"]},{"year":2007,"claim":"Established phosphorylation- and genotype-dependent control of ING1, defining Ser-126 phosphorylation as a stability switch and demonstrating both p53-dependent senescence and p53-independent tumor suppression in vivo.","evidence":"In vitro kinase assays (Chk1/Cdk1), Ser126Ala mutagenesis with half-life measurement, and Ing1-knockout mice and MEFs","pmids":["17585055","17693408","17332334"],"confidence":"Medium","gaps":["Effector pathway for p53-independent suppression incompletely defined","Mechanism connecting Ser-126 to stability not molecularly resolved at this stage"]},{"year":2008,"claim":"Provided the structural and trafficking framework for ING1 function, defining the PHD finger as an H3K4me3 reader and establishing lamin-A-, karyopherin-, and NQO1-dependent localization and stability control.","evidence":"X-ray crystallography with mutagenesis, peptide microarray, LMNA-knockout cells, NLS mutagenesis, and in vitro proteasomal degradation assays","pmids":["18533182","18836436","18655775","18388957"],"confidence":"High","gaps":["How H3K4me3 reading is coupled to complex recruitment in vivo not fully defined","Hierarchy among localization controls unresolved"]},{"year":2010,"claim":"Identified chromatin-level transcriptional targets of ING1 (DGCR8) genome-wide, connecting its chromatin function to proliferation control.","evidence":"Expression microarray in Ing1-null MEFs, ChIP at the DGCR8 promoter, and proliferation assays","pmids":["20179197"],"confidence":"Medium","gaps":["Direct vs indirect regulation of broader target set unclear","Chromatin complex used at DGCR8 not specified"]},{"year":2011,"claim":"Defined the molecular basis of ING1-mediated p53 stabilization and its role in p16INK4a-driven senescence, linking ubiquitin binding and HAUSP recruitment to tumor-suppressor output.","evidence":"Ubiquitin-binding/Kd measurements, ING1-HAUSP Co-IP, p53 ubiquitination assays, and p16 ChIP with curcumin inhibition","pmids":["21731648","21896275"],"confidence":"Medium","gaps":["Whether HAUSP recruitment is constitutive or signal-induced not defined","Single lab for both findings"]},{"year":2013,"claim":"Broadened ING1 mechanism to DNA demethylation targeting, p53-independent mitochondrial apoptosis via BAX, and Src-driven cytoplasmic relocalization, defining cytoplasmic and chromatin axes beyond p53.","evidence":"Xenopus Ing1 knockdown with methylation/ChIP analysis, ING1-BAX Co-IP with mitochondria-targeted constructs, and Src in vitro kinase plus Co-IP and apoptosis assays","pmids":["23388825","24008732","23585863"],"confidence":"Medium","gaps":["BH3-like domain function not structurally validated","Relationship between nuclear and mitochondrial pools unresolved"]},{"year":2017,"claim":"Established ING1 as a direct repressor of rRNA transcription, linking it to ribosome biogenesis control via HDAC1/NoRC recruitment and mTOR antagonism at the nucleolus.","evidence":"ChIP of ING1/HDAC1/NoRC at rDNA, Co-IP, rRNA quantification, and mTOR localization imaging with knockdown","pmids":["27903908"],"confidence":"Medium","gaps":["Mechanism of ING1-mTOR/UBF antagonism not biochemically defined","Single lab"]},{"year":2021,"claim":"Showed ING1 mediates androgen-receptor-dependent repression of hTERT, extending its repressive chromatin role to hormone-regulated transcription.","evidence":"ChIP at the hTERT nARE, reporter assays, siRNA knockdown, and ex vivo patient samples","pmids":["34439179"],"confidence":"Medium","gaps":["Whether ING1 reads a specific chromatin mark at the nARE not defined","Functional redundancy with ING2 unresolved"]},{"year":null,"claim":"How the single H3K4me3-reading PHD finger is dynamically switched between activating HAT and repressive HDAC complexes, and how nuclear, nucleolar, and mitochondrial pools are coordinated during the damage response, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ING1 within an intact HAT or HDAC complex","Determinants of complex selection in vivo unknown","Quantitative coordination of subcellular pools during apoptosis not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[21,26,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,13,15,33,37]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[14,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,13,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[27,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,23,22]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[9,17,29,33]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,32]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[26,19]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7,11,12,13,33]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,15,25,37]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,8,31]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10,21,30]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,19,26]}],"complexes":["Sin3-HDAC1 (mSin3A/SAP30/RbAp48)","NuA4 HAT complex","NoRC"],"partners":["TP53","PCNA","SAP30","HDAC1","LMNA","BAX","USP7/HAUSP","GADD45A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UK53","full_name":"Inhibitor of growth protein 1","aliases":[],"length_aa":422,"mass_kda":46.7,"function":"Cooperates with p53/TP53 in the negative regulatory pathway of cell growth by modulating p53-dependent transcriptional activation. Implicated as a tumor suppressor gene","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UK53/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ING1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ING1","total_profiled":1310},"omim":[{"mim_id":"618514","title":"BRMS1-LIKE TRANSCRIPTIONAL REPRESSOR; BRMS1L","url":"https://www.omim.org/entry/618514"},{"mim_id":"610696","title":"PCNA CLAMP-ASSOCIATED FACTOR; PCLAF","url":"https://www.omim.org/entry/610696"},{"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":"607493","title":"INHIBITOR OF GROWTH 3; ING3","url":"https://www.omim.org/entry/607493"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ING1"},"hgnc":{"alias_symbol":["p33ING1","p33ING1b","p24ING1c","p33","p47","p47ING1a"],"prev_symbol":[]},"alphafold":{"accession":"Q9UK53","domains":[{"cath_id":"3.30.40.10","chopping":"367-422","consensus_level":"high","plddt":80.9861,"start":367,"end":422},{"cath_id":"1.20.58","chopping":"186-262","consensus_level":"medium","plddt":91.8475,"start":186,"end":262}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK53","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK53-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK53-F1-predicted_aligned_error_v6.png","plddt_mean":57.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ING1","jax_strain_url":"https://www.jax.org/strain/search?query=ING1"},"sequence":{"accession":"Q9UK53","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UK53.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UK53/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK53"}},"corpus_meta":[{"pmid":"8944021","id":"PMC_8944021","title":"Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation.","date":"1996","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8944021","citation_count":266,"is_preprint":false},{"pmid":"9440695","id":"PMC_9440695","title":"The candidate tumour suppressor p33ING1 cooperates with p53 in cell growth control.","date":"1998","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9440695","citation_count":263,"is_preprint":false},{"pmid":"11784859","id":"PMC_11784859","title":"Role of the Sin3-histone deacetylase complex in growth regulation by the candidate tumor suppressor p33(ING1).","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11784859","citation_count":192,"is_preprint":false},{"pmid":"12446115","id":"PMC_12446115","title":"Different HATS of the ING1 gene family.","date":"2002","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12446115","citation_count":149,"is_preprint":false},{"pmid":"9102209","id":"PMC_9102209","title":"A novel candidate tumor suppressor, ING1, is involved in the regulation of apoptosis.","date":"1997","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9102209","citation_count":141,"is_preprint":false},{"pmid":"11682605","id":"PMC_11682605","title":"UV-induced binding of ING1 to PCNA regulates the induction of apoptosis.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11682605","citation_count":141,"is_preprint":false},{"pmid":"10805724","id":"PMC_10805724","title":"Three yeast proteins related to the human candidate tumor suppressor p33(ING1) are associated with histone acetyltransferase activities.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10805724","citation_count":141,"is_preprint":false},{"pmid":"9121449","id":"PMC_9121449","title":"Extension of the replicative life span of human diploid fibroblasts by inhibition of the p33ING1 candidate tumor suppressor.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9121449","citation_count":136,"is_preprint":false},{"pmid":"10866301","id":"PMC_10866301","title":"Genomic structure of the human ING1 gene and tumor-specific mutations detected in head and neck squamous cell carcinomas.","date":"2000","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10866301","citation_count":131,"is_preprint":false},{"pmid":"10498868","id":"PMC_10498868","title":"Suppression of ING1 expression in sporadic breast cancer.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10498868","citation_count":124,"is_preprint":false},{"pmid":"11118440","id":"PMC_11118440","title":"Differential association of products of alternative transcripts of the candidate tumor suppressor ING1 with the mSin3/HDAC1 transcriptional corepressor complex.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11118440","citation_count":119,"is_preprint":false},{"pmid":"18533182","id":"PMC_18533182","title":"Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18533182","citation_count":111,"is_preprint":false},{"pmid":"12015309","id":"PMC_12015309","title":"Human ING1 proteins differentially regulate histone acetylation.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12015309","citation_count":104,"is_preprint":false},{"pmid":"11353074","id":"PMC_11353074","title":"UV induces nucleolar translocation of ING1 through two distinct nucleolar targeting sequences.","date":"2001","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11353074","citation_count":103,"is_preprint":false},{"pmid":"11431327","id":"PMC_11431327","title":"The tumor suppressor candidate p33(ING1) mediates repair of UV-damaged DNA.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11431327","citation_count":99,"is_preprint":false},{"pmid":"10626813","id":"PMC_10626813","title":"Cancer-testis antigens and ING1 tumor suppressor gene product are breast cancer antigens: characterization of tissue-specific ING1 transcripts and a homologue gene.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10626813","citation_count":97,"is_preprint":false},{"pmid":"14522900","id":"PMC_14522900","title":"ING1 represses transcription by direct DNA binding and through effects on p53.","date":"2003","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/14522900","citation_count":93,"is_preprint":false},{"pmid":"11604499","id":"PMC_11604499","title":"Role of an ING1 growth regulator in transcriptional activation and targeted histone acetylation by the NuA4 complex.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11604499","citation_count":91,"is_preprint":false},{"pmid":"10554029","id":"PMC_10554029","title":"Adenovirus-mediated transfer of p33ING1 with p53 drastically augments apoptosis in gliomas.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10554029","citation_count":88,"is_preprint":false},{"pmid":"18836436","id":"PMC_18836436","title":"Tethering by lamin A stabilizes and targets the ING1 tumour suppressor.","date":"2008","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18836436","citation_count":79,"is_preprint":false},{"pmid":"11389058","id":"PMC_11389058","title":"Genetic alterations of candidate tumor suppressor ING1 in human esophageal squamous cell cancer.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11389058","citation_count":78,"is_preprint":false},{"pmid":"10660101","id":"PMC_10660101","title":"Reduced expression of p33(ING1) and the relationship with p53 expression in human gastric cancer.","date":"1999","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/10660101","citation_count":77,"is_preprint":false},{"pmid":"17332334","id":"PMC_17332334","title":"Deletion of p37Ing1 in mice reveals a p53-independent role for Ing1 in the suppression of cell proliferation, apoptosis, and tumorigenesis.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17332334","citation_count":73,"is_preprint":false},{"pmid":"18388957","id":"PMC_18388957","title":"NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of the tumour suppressor p33(ING1b).","date":"2008","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/18388957","citation_count":68,"is_preprint":false},{"pmid":"9186514","id":"PMC_9186514","title":"Cellular localization and chromosome mapping of a novel candidate tumor suppressor gene (ING1).","date":"1997","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9186514","citation_count":66,"is_preprint":false},{"pmid":"10542254","id":"PMC_10542254","title":"Structure and regulation of the mouse ing1 gene. Three alternative transcripts encode two phd finger proteins that have opposite effects on p53 function.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10542254","citation_count":62,"is_preprint":false},{"pmid":"21528065","id":"PMC_21528065","title":"Down-regulation of miR-622 in gastric cancer promotes cellular invasion and tumor metastasis by targeting ING1 gene.","date":"2011","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/21528065","citation_count":62,"is_preprint":false},{"pmid":"10072587","id":"PMC_10072587","title":"Cloning of a novel gene (ING1L) homologous to ING1, a candidate tumor suppressor.","date":"1998","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10072587","citation_count":62,"is_preprint":false},{"pmid":"10577281","id":"PMC_10577281","title":"Decreased expression of p33ING1 mRNA in lymphoid malignancies.","date":"1999","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/10577281","citation_count":61,"is_preprint":false},{"pmid":"12154053","id":"PMC_12154053","title":"ING1 isoforms differentially affect apoptosis in a cell age-dependent manner.","date":"2002","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12154053","citation_count":61,"is_preprint":false},{"pmid":"16170338","id":"PMC_16170338","title":"Targeted disruption of the mouse ing1 locus results in reduced body size, hypersensitivity to radiation and elevated incidence of lymphomas.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16170338","citation_count":61,"is_preprint":false},{"pmid":"15569986","id":"PMC_15569986","title":"ING-1, a monoclonal antibody targeting Ep-CAM in patients with advanced adenocarcinomas.","date":"2004","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/15569986","citation_count":58,"is_preprint":false},{"pmid":"16288740","id":"PMC_16288740","title":"The PCNA-associated factor KIAA0101/p15(PAF) binds the potential tumor suppressor product p33ING1b.","date":"2005","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/16288740","citation_count":54,"is_preprint":false},{"pmid":"10754201","id":"PMC_10754201","title":"Diminished expression of ING1 mRNA and the correlation with p53 expression in breast cancers.","date":"2000","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/10754201","citation_count":53,"is_preprint":false},{"pmid":"23412501","id":"PMC_23412501","title":"ING1 and ING2: multifaceted tumor suppressor genes.","date":"2013","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/23412501","citation_count":52,"is_preprint":false},{"pmid":"12243754","id":"PMC_12243754","title":"p33(ING1) enhances UVB-induced apoptosis in melanoma cells.","date":"2002","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/12243754","citation_count":51,"is_preprint":false},{"pmid":"16581770","id":"PMC_16581770","title":"Subcellular targeting of p33ING1b by phosphorylation-dependent 14-3-3 binding regulates p21WAF1 expression.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16581770","citation_count":50,"is_preprint":false},{"pmid":"10807544","id":"PMC_10807544","title":"p24/ING1-ALT1 and p47/ING1-ALT2, distinct alternative transcripts of p33/ING1.","date":"2000","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10807544","citation_count":48,"is_preprint":false},{"pmid":"30302016","id":"PMC_30302016","title":"Nitazoxanide, an antiprotozoal drug, inhibits late-stage autophagy and promotes ING1-induced cell cycle arrest in glioblastoma.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30302016","citation_count":47,"is_preprint":false},{"pmid":"10679922","id":"PMC_10679922","title":"Molecular analysis of the candidate tumor suppressor gene ING1 in human head and neck tumors with 13q deletions.","date":"2000","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10679922","citation_count":47,"is_preprint":false},{"pmid":"14676120","id":"PMC_14676120","title":"Altered subcellular localization and low frequency of mutations of ING1 in human brain tumors.","date":"2003","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/14676120","citation_count":45,"is_preprint":false},{"pmid":"11076655","id":"PMC_11076655","title":"Expression of the novel tumour suppressor p33(ING1)is independent of p53.","date":"2000","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11076655","citation_count":44,"is_preprint":false},{"pmid":"11461112","id":"PMC_11461112","title":"The tumor suppressor ING1: structure and function.","date":"2001","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11461112","citation_count":43,"is_preprint":false},{"pmid":"15601862","id":"PMC_15601862","title":"Growth inhibition by the tumor suppressor p33ING1 in immortalized and primary cells: involvement of two silencing domains and effect of Ras.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15601862","citation_count":43,"is_preprint":false},{"pmid":"23388825","id":"PMC_23388825","title":"Ing1 functions in DNA demethylation by directing Gadd45a to H3K4me3.","date":"2013","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/23388825","citation_count":42,"is_preprint":false},{"pmid":"11956069","id":"PMC_11956069","title":"Identification of the p33(ING1)-regulated genes that include cyclin B1 and proto-oncogene DEK by using cDNA microarray in a mouse mammary epithelial cell line NMuMG.","date":"2002","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11956069","citation_count":42,"is_preprint":false},{"pmid":"11850840","id":"PMC_11850840","title":"Facilitation of adenoviral wild-type p53-induced apoptotic cell death by overexpression of p33(ING1) in T.Tn human esophageal carcinoma cells.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11850840","citation_count":41,"is_preprint":false},{"pmid":"17585055","id":"PMC_17585055","title":"Phosphorylation of the tumor suppressor p33(ING1b) at Ser-126 influences its protein stability and proliferation of melanoma cells.","date":"2007","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17585055","citation_count":41,"is_preprint":false},{"pmid":"15677627","id":"PMC_15677627","title":"Epigenetic and genetic alterations of p33ING1b in ovarian cancer.","date":"2005","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/15677627","citation_count":39,"is_preprint":false},{"pmid":"21731648","id":"PMC_21731648","title":"The p53 tumor suppressor is stabilized by inhibitor of growth 1 (ING1) by blocking polyubiquitination.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21731648","citation_count":37,"is_preprint":false},{"pmid":"16465410","id":"PMC_16465410","title":"Alterations in novel candidate tumor suppressor genes, ING1 and ING2 in human lung cancer.","date":"2006","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16465410","citation_count":36,"is_preprint":false},{"pmid":"12147653","id":"PMC_12147653","title":"Loss of nuclear expression of the p33(ING1b) inhibitor of growth protein in childhood acute lymphoblastic leukaemia.","date":"2002","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12147653","citation_count":36,"is_preprint":false},{"pmid":"11943021","id":"PMC_11943021","title":"Nuclear to cytoplasmic compartment shift of the p33ING1b tumour suppressor protein is associated with malignancy in melanocytic lesions.","date":"2002","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/11943021","citation_count":35,"is_preprint":false},{"pmid":"9330636","id":"PMC_9330636","title":"Localization of the candidate tumor suppressor gene ING1 to human chromosome 13q34.","date":"1997","source":"Somatic cell and molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9330636","citation_count":34,"is_preprint":false},{"pmid":"12835295","id":"PMC_12835295","title":"Downregulation of nuclear expression of the p33(ING1b) inhibitor of growth protein in invasive carcinoma of the breast.","date":"2003","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12835295","citation_count":34,"is_preprint":false},{"pmid":"15201991","id":"PMC_15201991","title":"Mutations of the ING1 tumor suppressor gene detected in human melanoma abrogate nucleotide excision repair.","date":"2004","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15201991","citation_count":33,"is_preprint":false},{"pmid":"11991811","id":"PMC_11991811","title":"Comparative assessment expression of the inhibitor of growth 1 gene (ING1) in normal and neoplastic tissues.","date":"2002","source":"Hybridoma and hybridomics","url":"https://pubmed.ncbi.nlm.nih.gov/11991811","citation_count":33,"is_preprint":false},{"pmid":"24008732","id":"PMC_24008732","title":"ING1 induces apoptosis through direct effects at the mitochondria.","date":"2013","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24008732","citation_count":31,"is_preprint":false},{"pmid":"21779982","id":"PMC_21779982","title":"The expression of p33(ING1), p53, and autophagy-related gene Beclin1 in patients with non-small cell lung cancer.","date":"2011","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21779982","citation_count":30,"is_preprint":false},{"pmid":"21078114","id":"PMC_21078114","title":"The tumor suppressor ING1 contributes to epigenetic control of cellular senescence.","date":"2010","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/21078114","citation_count":30,"is_preprint":false},{"pmid":"16607280","id":"PMC_16607280","title":"A functional link between the tumour suppressors ARF and p33ING1.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16607280","citation_count":30,"is_preprint":false},{"pmid":"20179197","id":"PMC_20179197","title":"Regulation of the microRNA processor DGCR8 by the tumor suppressor ING1.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20179197","citation_count":30,"is_preprint":false},{"pmid":"11966686","id":"PMC_11966686","title":"The novel tumour suppressor gene ING1 is overexpressed in human melanoma cell lines.","date":"2002","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/11966686","citation_count":29,"is_preprint":false},{"pmid":"12632089","id":"PMC_12632089","title":"Analyses of the tumour suppressor ING1 expression and gene mutation in human basal cell carcinoma.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12632089","citation_count":29,"is_preprint":false},{"pmid":"22916295","id":"PMC_22916295","title":"ING1 and 5-azacytidine act synergistically to block breast cancer cell growth.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22916295","citation_count":29,"is_preprint":false},{"pmid":"12523595","id":"PMC_12523595","title":"Expression of p33(ING1) in hepatocellular carcinoma: relationships to tumour differentiation and cyclin E kinase activity.","date":"2002","source":"Scandinavian journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/12523595","citation_count":29,"is_preprint":false},{"pmid":"14961591","id":"PMC_14961591","title":"No ING1 mutations in human brain tumours but reduced expression in high malignancy grades of astrocytoma.","date":"2004","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/14961591","citation_count":27,"is_preprint":false},{"pmid":"17693408","id":"PMC_17693408","title":"Ing1 mediates p53 accumulation and chromatin modification in response to oncogenic stress.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17693408","citation_count":27,"is_preprint":false},{"pmid":"10615239","id":"PMC_10615239","title":"The candidate tumour suppressor gene, ING1, is retained in colorectal carcinomas.","date":"1999","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/10615239","citation_count":27,"is_preprint":false},{"pmid":"10868796","id":"PMC_10868796","title":"A panel of CAb antibodies recognize endogenous and ectopically expressed ING1 protein.","date":"2000","source":"Hybridoma","url":"https://pubmed.ncbi.nlm.nih.gov/10868796","citation_count":27,"is_preprint":false},{"pmid":"17693421","id":"PMC_17693421","title":"Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, a human engineere monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors.","date":"2007","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17693421","citation_count":27,"is_preprint":false},{"pmid":"12820433","id":"PMC_12820433","title":"Expression of p33ING1 mRNA and chemosensitivity in brain tumor cells.","date":"2003","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12820433","citation_count":25,"is_preprint":false},{"pmid":"22419112","id":"PMC_22419112","title":"Nucleolar protein CSIG is required for p33ING1 function in UV-induced apoptosis.","date":"2012","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/22419112","citation_count":25,"is_preprint":false},{"pmid":"21896275","id":"PMC_21896275","title":"The tumor suppressor p33ING1b upregulates p16INK4a expression and induces cellular senescence.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21896275","citation_count":24,"is_preprint":false},{"pmid":"25613480","id":"PMC_25613480","title":"MicroRNA let-7b suppresses human gastric cancer malignancy by targeting ING1.","date":"2015","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/25613480","citation_count":23,"is_preprint":false},{"pmid":"15800978","id":"PMC_15800978","title":"Inhibitory effect of tumor suppressor p33(ING1b) and its synergy with p53 gene in hepatocellular carcinoma.","date":"2005","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15800978","citation_count":22,"is_preprint":false},{"pmid":"12637159","id":"PMC_12637159","title":"ING1 and p53 tumor suppressor gene alterations in adenocarcinomas of the esophagogastric junction.","date":"2003","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/12637159","citation_count":20,"is_preprint":false},{"pmid":"23585863","id":"PMC_23585863","title":"Src regulates the activity of the ING1 tumor suppressor.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23585863","citation_count":20,"is_preprint":false},{"pmid":"18655775","id":"PMC_18655775","title":"ING1 protein targeting to the nucleus by karyopherins is necessary for activation of p21.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18655775","citation_count":20,"is_preprint":false},{"pmid":"15375540","id":"PMC_15375540","title":"Dysfunction of p53 pathway in human colorectal cancer: analysis of p53 gene mutation and the expression of the p53-associated factors p14ARF, p33ING1, p21WAF1 and MDM2.","date":"2004","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15375540","citation_count":20,"is_preprint":false},{"pmid":"30372865","id":"PMC_30372865","title":"Down-regulation of miR-500 and miR-628 suppress non-small cell lung cancer proliferation, migration and invasion by targeting ING1.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30372865","citation_count":20,"is_preprint":false},{"pmid":"11287275","id":"PMC_11287275","title":"Mutational analysis of the candidate tumor suppressor gene ING1 in Indian oral squamous cell carcinoma.","date":"2001","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11287275","citation_count":20,"is_preprint":false},{"pmid":"11835353","id":"PMC_11835353","title":"Expression and sequence analyses of p33(ING1) gene in myeloid leukemia.","date":"2002","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/11835353","citation_count":19,"is_preprint":false},{"pmid":"27305909","id":"PMC_27305909","title":"A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling.","date":"2016","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/27305909","citation_count":19,"is_preprint":false},{"pmid":"27903908","id":"PMC_27903908","title":"ING1 regulates rRNA levels by altering nucleolar chromatin structure and mTOR localization.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27903908","citation_count":18,"is_preprint":false},{"pmid":"15955533","id":"PMC_15955533","title":"Multiple variants of the ING1 and ING2 tumor suppressors are differentially expressed and thyroid hormone-responsive in Xenopus laevis.","date":"2005","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15955533","citation_count":17,"is_preprint":false},{"pmid":"34439179","id":"PMC_34439179","title":"Antithetic hTERT Regulation by Androgens in Prostate Cancer Cells: hTERT Inhibition Is Mediated by the ING1 and ING2 Tumor Suppressors.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34439179","citation_count":17,"is_preprint":false},{"pmid":"16325212","id":"PMC_16325212","title":"The p33ING1b tumor suppressor cooperates with p53 to induce apoptosis in response to etoposide in human osteosarcoma cells.","date":"2005","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16325212","citation_count":16,"is_preprint":false},{"pmid":"9455706","id":"PMC_9455706","title":"Specific monoclonal antibody raised against the p33ING1 tumor suppressor.","date":"1997","source":"Hybridoma","url":"https://pubmed.ncbi.nlm.nih.gov/9455706","citation_count":16,"is_preprint":false},{"pmid":"15534913","id":"PMC_15534913","title":"Genetic alterations and reduced expression of tumor suppressor p33(ING1b) in human exocrine pancreatic carcinoma.","date":"2004","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15534913","citation_count":15,"is_preprint":false},{"pmid":"14630091","id":"PMC_14630091","title":"p33(ING1b) stimulates the transcriptional activity of the estrogen receptor alpha via its activation function (AF) 2 domain.","date":"2003","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14630091","citation_count":15,"is_preprint":false},{"pmid":"17805569","id":"PMC_17805569","title":"Nuclear to cytoplasmic shift of p33(ING1b) protein from normal oral mucosa to oral squamous cell carcinoma in relation to clinicopathological variables.","date":"2007","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17805569","citation_count":15,"is_preprint":false},{"pmid":"15662138","id":"PMC_15662138","title":"The tumor suppressor p33ING1b enhances taxol-induced apoptosis by p53-dependent pathway in human osteosarcoma U2OS cells.","date":"2005","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/15662138","citation_count":14,"is_preprint":false},{"pmid":"20681406","id":"PMC_20681406","title":"The inhibitor of growth 1 (ING1) is involved in trichostatin A-induced apoptosis and caspase 3 signaling in p53-deficient glioblastoma cells.","date":"2010","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/20681406","citation_count":14,"is_preprint":false},{"pmid":"24962136","id":"PMC_24962136","title":"Reduced ING1 levels in breast cancer promotes metastasis.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/24962136","citation_count":13,"is_preprint":false},{"pmid":"11888890","id":"PMC_11888890","title":"Mouse ING1 homologue, a protein interacting with A1, enhances cell death and is inhibited by A1 in mammary epithelial cells.","date":"2002","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11888890","citation_count":13,"is_preprint":false},{"pmid":"20066899","id":"PMC_20066899","title":"The inhibitor of growth 1 (ING1) proteins suppress angiogenesis and differentially regulate angiopoietin expression in glioblastoma cells.","date":"2009","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/20066899","citation_count":12,"is_preprint":false},{"pmid":"17763999","id":"PMC_17763999","title":"Down-regulation of the inhibitor of growth 1 (ING1) tumor suppressor sensitizes p53-deficient glioblastoma cells to cisplatin-induced cell death.","date":"2007","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17763999","citation_count":12,"is_preprint":false},{"pmid":"17949449","id":"PMC_17949449","title":"The predictive value of p53 and p33(ING1b) in patients with Dukes'C colorectal cancer.","date":"2007","source":"Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland","url":"https://pubmed.ncbi.nlm.nih.gov/17949449","citation_count":12,"is_preprint":false},{"pmid":"21286670","id":"PMC_21286670","title":"Genetic alterations of tumor suppressor ING1 in human non-small cell lung cancer.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21286670","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46262,"output_tokens":8751,"usd":0.135025,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18535,"output_tokens":5700,"usd":0.117587,"stage2_stop_reason":"end_turn"},"total_usd":0.252612,"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\": 1996,\n      \"finding\": \"ING1 (p33ING1) was identified as a nuclear growth inhibitor whose acute overexpression inhibits cell growth and whose chronic antisense suppression promotes neoplastic transformation, establishing it as a candidate tumor suppressor.\",\n      \"method\": \"Subtractive hybridization/GSE cloning; transfection overexpression and antisense chronic expression assays in cell lines\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (antisense) and gain-of-function (overexpression) in multiple cell systems, single lab but two orthogonal functional readouts\",\n      \"pmids\": [\"8944021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"p33ING1 protein localizes to the nucleus, consistent with its role as a growth regulator.\",\n      \"method\": \"Indirect immunofluorescence; fluorescence in situ hybridization for chromosomal localization\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence, replicated in subsequent studies\",\n      \"pmids\": [\"9186514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ING1 RNA and protein levels are 8–10-fold higher in senescent human diploid fibroblasts than in young cells; chronic antisense ING1 expression extends the proliferative lifespan by ~7 population doublings, establishing ING1 as a regulator of cellular senescence.\",\n      \"method\": \"Quantitative RT-PCR/Western blot; antisense chronic expression with proliferative lifespan measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and expression quantification, single lab\",\n      \"pmids\": [\"9121449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"p33ING1 promotes apoptosis: its levels increase upon apoptosis induction, overexpression enhances serum starvation-induced apoptosis synergistically with Myc, and antisense ING1 protects cells from apoptosis.\",\n      \"method\": \"Tetracycline-controlled c-myc system; antisense ING1 stable expression; apoptosis assays in P19 and fibroblast cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with apoptosis readout in multiple cell types, single lab\",\n      \"pmids\": [\"9102209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"p33ING1 physically associates with p53 by co-immunoprecipitation, and the biological growth-inhibitory effects of ING1 require active p53; ING1 cooperates with p53 to activate transcription from the p21/WAF1 promoter.\",\n      \"method\": \"Co-immunoprecipitation; p21/WAF1 promoter-luciferase reporter assays; antisense/dominant-negative suppression epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional epistasis plus physical interaction by Co-IP, replicated across multiple subsequent studies\",\n      \"pmids\": [\"9440695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The longer mouse ing1 isoform (p47 equivalent) forms a detectable complex with p53 by immunoprecipitation and interferes with p53 protein accumulation and p53-responsive promoter activation after DNA damage, while the shorter isoform (p33 equivalent) activates p53 responses — demonstrating that a single locus encodes both p53-suppressing and p53-activating proteins.\",\n      \"method\": \"Co-immunoprecipitation; p53-responsive promoter-reporter assays; Western blot after DNA damage\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter assays, single lab, mouse ortholog\",\n      \"pmids\": [\"10542254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Three yeast ING1 homologs (Yng1, Yng2, Pho23) co-immunoprecipitate with histone acetyltransferase (HAT) activity; Yng2 interacts with Tra1 (a NuA4 HAT complex component) by yeast two-hybrid and Co-IP, linking ING1-family proteins to HAT complexes and chromatin remodeling.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; HAT activity assays; yeast genetics (deletion phenotypes rescued by human ING1)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, Co-IP, in vitro HAT assay, genetic rescue), replicated for multiple homologs\",\n      \"pmids\": [\"10805724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"p33ING1b (but not p24ING1c) associates with the mSin3 transcriptional corepressor complex including Sin3, SAP30, HDAC1, and RbAp48; ING1 immune complexes deacetylate core histones in vitro; p33ING1b is functionally associated with HDAC1-mediated transcriptional repression.\",\n      \"method\": \"Co-immunoprecipitation; in vitro histone deacetylase assay; transcriptional repression reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical complex isolation, in vitro enzymatic assay, and functional reporter assay; replicated by independent lab (Kuzmichev 2002)\",\n      \"pmids\": [\"11118440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"UV irradiation rapidly induces p33ING1b to bind PCNA through a PCNA-interacting protein (PIP) domain; PIP mutants that cannot bind PCNA fail to induce apoptosis and instead protect cells from UV-induced apoptosis, establishing that ING1-PCNA interaction is required for UV-induced programmed cell death.\",\n      \"method\": \"Co-immunoprecipitation; PIP domain mutagenesis; apoptosis assays after UV; competitive inhibition by p21 overexpression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mutagenesis with defined functional readout (apoptosis), competitive inhibition control, multiple orthogonal methods\",\n      \"pmids\": [\"11682605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"UV irradiation induces nucleolar translocation of ING1 proteins; ING1 contains two distinct 4-amino-acid nucleolar targeting sequences (NTS); NTS mutants that fail to translocate to the nucleolus do not efficiently induce apoptosis and instead protect cells from UV-induced apoptosis.\",\n      \"method\": \"Live-cell imaging with GFP fusions; NTS deletion/point mutants; apoptosis assays; fluorescence microscopy\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by live imaging with functional consequence established by mutagenesis, replicated by multiple independent studies\",\n      \"pmids\": [\"11353074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"p33ING1b (ING1) enhances repair of UV-damaged DNA and physically interacts with GADD45; this DNA repair function requires p53.\",\n      \"method\": \"Host-cell-reactivation DNA repair assay; co-immunoprecipitation of ING1 and GADD45; overexpression/antisense experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional repair assay plus Co-IP interaction, single lab\",\n      \"pmids\": [\"11431327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Yng2p (yeast ING1 homolog) is a stable stoichiometric subunit of the NuA4 HAT complex; NuA4 from Δyng2 cells shows weak HAT activity; Yng2 PHD finger is required for full expression of p53-responsive genes and targeted NuA4-dependent histone H4 hyperacetylation.\",\n      \"method\": \"Mass spectrometry; immunoblotting; immunoprecipitation of purified NuA4; in vitro p53 interaction; histone acetylation assays in yeast\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of complex by MS + Co-IP, in vitro HAT assay, genetic deletion phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"11604499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"p33ING1b, but not p47ING1a, interacts with HAT-associated proteins (TRRAP, PCAF, CBP, p300) and induces hyperacetylation of histones H3 and H4 in vitro and in vivo; p47ING1a inhibits histone acetylation and binds HDAC1; p33ING1b affects the PCNA-p300 physical association.\",\n      \"method\": \"Co-immunoprecipitation; in vitro HAT assays; in vivo single-cell histone acetylation imaging; Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, in vitro enzymatic assay, in vivo imaging), isoform-specific effects established\",\n      \"pmids\": [\"12015309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"p33ING1b associates with the Sin3-HDAC complex through direct interaction between its N-terminal domain and SAP30; two distinct Sin3-p33ING1b complexes exist, one of which additionally contains Brg1-based SWI/SNF subunits; growth suppression by p33ING1b requires the intact Sin3-HDAC-interacting domain.\",\n      \"method\": \"Co-immunoprecipitation; biochemical complex purification; domain deletion/interaction mapping; growth suppression assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical complex purification, domain mapping of direct interaction, functional domain requirement established\",\n      \"pmids\": [\"11784859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p33ING1b represses AFP promoter transcription by binding AT-motifs and excluding HNF1, and also by physically interacting with hSIR2 (SIRT1) to inhibit its deacetylase activity, thereby increasing acetylation of p53 at Lys373/382 and enhancing p53-dependent transcription.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA); promoter-reporter assays; co-immunoprecipitation; p53 acetylation Western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus EMSA plus functional reporter assays, single lab\",\n      \"pmids\": [\"14522900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p33ING1b contains two autonomous transcriptional silencing domains: an N-terminal domain whose silencing is HDAC-dependent (sensitive to TSA) and a C-terminal domain whose silencing is HDAC-independent (TSA-resistant); oncogenic Ras enhances ING1-mediated silencing through the MAP kinase pathway.\",\n      \"method\": \"Transcriptional reporter assays with deletion mutants; TSA and MAP kinase inhibitor treatment; colony formation assays; thymidine incorporation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with functional readout, pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"15601862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"p33ING1b interacts with 14-3-3 family proteins in a phosphorylation-dependent manner, causing significant cytoplasmic tethering of ING1b; overexpression of 14-3-3 inhibits ING1b-mediated induction of p21WAF1 after UV damage, demonstrating that subcellular mislocalization blocks ING1 biological activity.\",\n      \"method\": \"Co-immunoprecipitation; phosphatase treatment; subcellular fractionation; p21WAF1 Western blot; bioinformatics NLS/14-3-3 motif analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with phosphorylation dependency, fractionation, functional p21 readout, single lab\",\n      \"pmids\": [\"16581770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ARF physically interacts with p33ING1 in vivo, displaces ING1 from nuclear to nucleolar localization, and ARF-deficient primary fibroblasts show impaired ING1-mediated cell cycle arrest and p21CIP1/Mdm2 induction.\",\n      \"method\": \"Co-immunoprecipitation in vivo; fluorescence microscopy; ARF knockout MEFs; cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus localization plus genetic loss-of-function epistasis, single lab\",\n      \"pmids\": [\"16607280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Phosphorylation of p33ING1b at Ser-126 stabilizes the protein; Chk1 phosphorylates Ser-126 predominantly upon DNA damage while Cdk1 does so under basal conditions; mutation of Ser-126 to Ala dramatically shortens ING1b half-life and alters cyclin B1 expression and melanoma cell proliferation.\",\n      \"method\": \"In vitro kinase assays with Chk1 and Cdk1; pulse-chase/half-life measurement; Ser126Ala mutagenesis; cyclin B1 Western blot; proliferation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis with protein stability and functional readouts, single lab but multiple methods\",\n      \"pmids\": [\"17585055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ing1-deficient mouse embryonic fibroblasts show defective senescence-like antiproliferative response to oncogenic Ras, reduced p53 protein stability, and impaired heterochromatin formation during oncogene-induced senescence.\",\n      \"method\": \"Ing1 knockout MEFs; oncogenic Ras expression; p53 stability assays; heterochromatin mark immunostaining; senescence assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"17693408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p37Ing1 (mouse ING1) suppresses cell proliferation in a p53-independent manner; loss of p37Ing1 induces Bax expression and increases DNA damage-induced apoptosis irrespective of p53 status; p37Ing1 suppresses spontaneous follicular B-cell lymphomas in mice.\",\n      \"method\": \"p37Ing1 knockout mice; proliferation assays in p53 wild-type and p53-null backgrounds; Bax Western blot; tumor incidence monitoring\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in defined p53-null background establishes p53-independence, multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"17332334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The ING1 PHD finger binds histone H3 trimethylated at Lys4 (H3K4me3) but not other histone modifications; a 2.1 Å crystal structure reveals that Y212 and W235 form a hydrophobic pocket making cation-π contacts with the trimethylammonium group; W235A and cancer-associated mutations (N216S, V218I, G221V) disrupt H3K4me3 binding and abolish ING1's ability to stimulate DNA repair and promote apoptosis.\",\n      \"method\": \"Peptide microarray; X-ray crystallography (2.1 Å); site-directed mutagenesis; UV-induced DNA repair assay (host-cell reactivation); apoptosis assays in stable melanoma cell clones\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation plus functional rescue experiments; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"18533182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ING1 proteins contain a lamin interaction domain (LID) through which they bind and colocalize with lamin A; LMNA-/- cells show reduced ING1 levels and ING1 mislocalization; ectopic lamin A re-targets ING1 to the nucleus; ING1 lacking the LID does not interact with lamin A and cannot affect apoptosis.\",\n      \"method\": \"Co-immunoprecipitation; lamin A knockout cells; ectopic lamin A expression; GFP-ING1 localization imaging; LID deletion mutagenesis; apoptosis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, genetic knockout, domain mutagenesis, and functional apoptosis readout; multiple orthogonal methods\",\n      \"pmids\": [\"18836436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p33ING1b interacts with nuclear import machinery (karyopherins alpha2 and beta1) through basic NLS sequences adjacent to its PHD domain; deletion of NLS motifs prevents complete nuclear localization and abolishes ING1b-induced p21WAF1 expression.\",\n      \"method\": \"Co-immunoprecipitation; NLS deletion mutagenesis; subcellular localization imaging; p21WAF1 Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"18655775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p33ING1b is degraded by the 20S proteasome; NQO1 inhibits its proteasomal degradation; UV irradiation induces phosphorylation at Ser-126, which facilitates ING1b interaction with NQO1 and thereby stabilizes the protein.\",\n      \"method\": \"Proteasome inhibitors; partial proteasome complex isolation; in vitro degradation assays; in vitro interaction assays; NQO1 co-immunoprecipitation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro degradation reconstitution, complex isolation, and interaction assays; multiple complementary biochemical methods\",\n      \"pmids\": [\"18388957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ING1 binds to the DGCR8 promoter and represses its transcription through chromatin regulation; ING1 and DGCR8 cooperate to restrain cell proliferation.\",\n      \"method\": \"Genome-wide expression microarray in Ing1-null MEFs; chromatin immunoprecipitation (ChIP) at DGCR8 promoter; proliferation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional proliferation assay, genome-wide expression context, single lab\",\n      \"pmids\": [\"20179197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p33ING1b triggers cellular senescence in a p53-dependent manner in human primary fibroblasts; endogenous ING1 accumulates in chromatin in oncogene-induced senescent cells; recognition of H3K4me3 by the PHD finger is required for ING1-induced senescence; a tumor-derived ING1 mutant fails to induce senescence.\",\n      \"method\": \"RNAi knockdown; PHD-finger point mutants; oncogene-induced senescence assays; chromatin fractionation; gene expression profiling\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with functional senescence readout plus chromatin fractionation, single lab\",\n      \"pmids\": [\"21078114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ING1 stabilizes wild-type p53 by blocking its polyubiquitination; ING1 contains a ubiquitin-binding domain (UBD) overlapping its polybasic region (PBR) that binds ubiquitin with high affinity (Kd ~100 nM); ING1 physically interacts with the deubiquitinase HAUSP; knockdown of HAUSP blocks ING1-mediated p53 stabilization.\",\n      \"method\": \"Ubiquitin-binding assays; co-immunoprecipitation of ING1-HAUSP; p53 ubiquitination Western blots; ING1 knockdown; affinity binding measurements\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, biochemical binding assay with Kd measurement, and genetic knockdown with functional readout; single lab\",\n      \"pmids\": [\"21731648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p33ING1b upregulates p16INK4a transcription to induce cellular senescence; p33ING1b and the HAT p300 bind to the p16INK4a promoter; the p300/CBP inhibitor curcumin reverses p16INK4a induction by p33ING1b.\",\n      \"method\": \"Overexpression; RT-PCR/Western blot for p16; chromatin immunoprecipitation (ChIP); pharmacological inhibition\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and pharmacological inhibition with functional readout, single lab\",\n      \"pmids\": [\"21896275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"After UV irradiation, p33ING1 translocates into the nucleolus and binds the nucleolar protein CSIG; this interaction requires ING1's nucleolar targeting sequence; ING1 enhances CSIG protein stability; the ING1-CSIG complex promotes apoptosis via Bax activation.\",\n      \"method\": \"Co-immunoprecipitation; fluorescence microscopy; UV irradiation; Western blot for CSIG stability; apoptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus localization plus functional apoptosis readout, single lab\",\n      \"pmids\": [\"22419112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ING1 (Ing1) is required for targeting active DNA demethylation by recruiting the DNA demethylation regulator Gadd45a to H3K4me3-marked chromatin; reduced H3K4 methylation impairs Gadd45a/Ing1 recruitment and gene-specific DNA demethylation.\",\n      \"method\": \"Xenopus laevis model; Ing1 knockdown; Gadd45a recruitment assays; DNA methylation analysis; H3K4me3 ChIP\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with DNA methylation readout and ChIP in Xenopus, single lab\",\n      \"pmids\": [\"23388825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ING1 translocates to the mitochondria in response to apoptosis-inducing stimuli independently of p53; endogenous ING1 physically interacts with BAX and colocalizes with BAX upon UV in a UV-inducible manner; mitochondria-targeted ING1 induces apoptosis more efficiently than wild-type ING1; ING1 contains a BH3-like domain.\",\n      \"method\": \"Subcellular fractionation; co-immunoprecipitation of ING1 and BAX; mitochondria-targeted ING1 construct; apoptosis assays in multiple breast cancer cell lines; immunofluorescence colocalization\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus fractionation plus targeted construct functional comparison; single lab, multiple cell lines\",\n      \"pmids\": [\"24008732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Src tyrosine kinase physically associates with and phosphorylates ING1 both in vitro and in vivo, causing nuclear-to-cytoplasmic relocalization and decreased ING1 stability; Src antagonizes ING1-induced apoptosis through both kinase-dependent and kinase-independent mechanisms.\",\n      \"method\": \"In vitro kinase assay; co-immunoprecipitation; subcellular localization imaging; apoptosis assays; kinase-dead Src controls\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus Co-IP plus functional apoptosis readout, single lab\",\n      \"pmids\": [\"23585863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ING1b binds rDNA chromatin, recruits HDAC1 to rDNA loci, increases association of rDNA with the NoRC repressor complex, deacetylates active histone marks H3K9 and H3K27 on rDNA, and thereby represses rRNA/rDNA transcription; loss of ING1 enhances nucleolar localization of phospho-mTOR and its association with Raptor and GβL; ING1 inhibits UBF activity and the UBF-mTOR interaction.\",\n      \"method\": \"ChIP of ING1, HDAC1, NoRC, H3K9ac, H3K27ac at rDNA; co-immunoprecipitation; rRNA quantification; mTOR localization imaging; knockdown experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus rRNA functional readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27903908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse ING1 homolog (mINGh) physically interacts with the anti-apoptotic protein A1/Bfl-1 (identified by yeast two-hybrid); mINGh enhances cell death in mammary epithelial cells and this effect is inhibited by A1, placing ING1 in a functional antagonism with A1 in apoptosis regulation.\",\n      \"method\": \"Yeast two-hybrid screen; apoptosis assays in HC11 mammary epithelial cells; A1 overexpression co-transfection\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid interaction with functional co-expression assay, single lab, no confirmatory Co-IP in mammalian cells reported in abstract\",\n      \"pmids\": [\"11888890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The PCNA-associated protein p15PAF interacts with p33ING1b in the same complex in cell cultures; this interaction is detected by co-immunoprecipitation and both proteins show UV-enhanced association.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence colocalization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, no mechanistic follow-up in abstract\",\n      \"pmids\": [\"16288740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p33ING1b weakly physically associates with estrogen receptor alpha (ERα) in vitro and enhances estrogen-induced ERα transcriptional activity through the AF2 domain of ERα, acting as a coactivator.\",\n      \"method\": \"In vitro translated protein interaction assay; ERα transcriptional reporter assays; AF2 deletion mutant analysis\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro pull-down and reporter assay only, weak interaction noted, single lab\",\n      \"pmids\": [\"14630091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ING1 and ING2 are recruited to a negative androgen response element (nARE) in the hTERT promoter in an androgen-dependent manner and mediate AR-regulated transcriptional repression of hTERT; ING1 and ING2 knockdown impairs this repression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); promoter-reporter assays; siRNA knockdown; ex vivo patient samples\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown with reporter assay plus ex vivo validation, single lab\",\n      \"pmids\": [\"34439179\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ING1 (primarily the p33ING1b isoform) is a nuclear tumor suppressor that functions as an epigenetic 'reader' by binding H3K4me3 through its PHD finger domain, thereby targeting histone acetyltransferase (HAT; e.g., NuA4/TRRAP/p300/CBP) and histone deacetylase (HDAC; Sin3-HDAC1 via SAP30) complexes to chromatin to regulate transcription, DNA repair, and apoptosis; it physically associates with and cooperates with p53 to activate p21WAF1 and promote growth arrest, stabilizes p53 by recruiting the deubiquitinase HAUSP to block polyubiquitination, binds PCNA through a PIP domain upon UV damage to promote apoptosis, is targeted to the nucleus by lamin A (via a lamin interaction domain) and by karyopherins, is regulated by phosphorylation (Chk1/Cdk1 at Ser-126) that stabilizes it via NQO1 and modulates 14-3-3-dependent cytoplasmic sequestration, translocates to mitochondria to interact with BAX and promote p53-independent apoptosis, and recruits HDAC1 to rDNA to repress rRNA transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ING1 is a nuclear tumor suppressor that couples epigenetic chromatin reading to the control of proliferation, senescence, DNA repair, and apoptosis [#0, #2, #21]. Its PHD finger is a sequence-specific reader of histone H3 trimethylated at Lys4 (H3K4me3): a 2.1 Å structure shows Y212 and W235 forming a hydrophobic pocket that engages the trimethylammonium group through cation-π contacts, and cancer-associated PHD mutations abolish H3K4me3 binding and disable ING1's ability to stimulate DNA repair and promote apoptosis [#21]. Through this reader function ING1 docks chromatin-modifying machinery, partitioning between activating histone acetyltransferase complexes (NuA4/Tra1, TRRAP/PCAF/CBP/p300), which it uses to drive H3/H4 hyperacetylation in an isoform-specific manner, and repressive Sin3-HDAC1 complexes, which the p33ING1b N-terminus engages directly via SAP30 to silence transcription [#6, #11, #12, #13]. ING1 acts largely in concert with p53: it physically associates with p53, cooperates to transactivate p21WAF1 and drive growth arrest, stabilizes wild-type p53 by binding ubiquitin through a UBD and recruiting the deubiquitinase HAUSP to block polyubiquitination, and is required for oncogene-induced senescence and p53-dependent heterochromatin formation [#4, #19, #26, #27]. The shorter and longer ING1 isoforms have opposing effects on p53, so a single locus encodes both p53-activating and p53-suppressing proteins [#5]. ING1 also operates p53-independently, suppressing proliferation, inducing Bax, and translocating to mitochondria where, via a BH3-like domain, it interacts with BAX to promote apoptosis [#20, #31]. ING1 activity is gated by localization and stability: it requires a lamin-A interaction domain and karyopherin-dependent nuclear import, undergoes UV-induced nucleolar translocation to bind PCNA (via a PIP domain) and CSIG to commit cells to apoptosis, and is regulated by phosphorylation at Ser-126 (by Chk1 and Cdk1) that stabilizes it through NQO1, while 14-3-3 binding and Src-mediated phosphorylation drive cytoplasmic sequestration that blocks its function [#8, #9, #16, #18, #22, #23, #24, #29, #32]. At the nucleolus ING1b recruits HDAC1 and the NoRC complex to rDNA to deacetylate active marks and repress rRNA transcription [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established ING1 as a candidate tumor suppressor by showing its expression bidirectionally controls cell growth, addressing whether the gene actively restrains proliferation.\",\n      \"evidence\": \"Subtractive/GSE cloning with overexpression and chronic antisense in cell lines\",\n      \"pmids\": [\"8944021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for growth inhibition\", \"Single lab functional readouts\", \"No in vivo tumor data\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linked ING1 to senescence and apoptosis, defining the cellular programs it engages beyond simple growth inhibition.\",\n      \"evidence\": \"Immunofluorescence localization, expression quantification in senescent fibroblasts, and antisense/overexpression apoptosis assays\",\n      \"pmids\": [\"9186514\", \"9121449\", \"9102209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular effectors identified\", \"Mechanism of senescence/apoptosis induction unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed ING1 physically and functionally cooperates with p53 to activate p21WAF1, placing it within the p53 growth-arrest pathway.\",\n      \"evidence\": \"Co-IP, p21/WAF1 promoter-reporter assays, and antisense/dominant-negative epistasis\",\n      \"pmids\": [\"9440695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect p53 binding not resolved\", \"Did not address p53-independent functions\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Revealed that the ING1 locus encodes isoforms with opposing effects on p53, explaining functional heterogeneity within the gene.\",\n      \"evidence\": \"Co-IP and p53-responsive reporter assays after DNA damage with mouse isoforms\",\n      \"pmids\": [\"10542254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of opposing isoform activity unclear\", \"Mouse ortholog only\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Connected ING1-family proteins to histone acetyltransferase and Sin3-HDAC corepressor complexes, defining ING1 as a chromatin-modifying complex component.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, HAT activity assays, genetic rescue, in vitro HDAC assays, and reporter assays\",\n      \"pmids\": [\"10805724\", \"11118440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ING1 selects HAT vs HDAC complexes not defined\", \"Chromatin targeting determinant unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the DNA-damage response axis of ING1, linking UV-induced PCNA binding and nucleolar targeting to commitment to apoptosis and DNA repair.\",\n      \"evidence\": \"PIP and NTS domain mutagenesis with apoptosis assays, host-cell reactivation repair assays, GADD45 Co-IP, and NuA4 reconstitution by MS in yeast\",\n      \"pmids\": [\"11682605\", \"11353074\", \"11431327\", \"11604499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PCNA binding switches repair to apoptosis unresolved\", \"Nucleolar effectors not yet identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped isoform-specific partitioning between acetylation-promoting and deacetylation-promoting complexes via direct SAP30 binding, defining how ING1 imposes activating or repressive chromatin states.\",\n      \"evidence\": \"Co-IP, in vitro HAT assays, in vivo acetylation imaging, complex purification, and domain-mapping growth suppression assays\",\n      \"pmids\": [\"12015309\", \"11784859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of complex selection not defined\", \"Determinants directing isoform-specific partner choice unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended ING1's reach to SIRT1 inhibition and promoter-specific DNA binding, showing it tunes p53 acetylation and represses target promoters.\",\n      \"evidence\": \"EMSA, promoter-reporter assays, Co-IP, and p53 acetylation Western blots\",\n      \"pmids\": [\"14522900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SIRT1 inhibition mechanism not structurally defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined two autonomous silencing domains with distinct HDAC dependence and showed oncogenic Ras enhances ING1 silencing, integrating signaling input into its repressive function.\",\n      \"evidence\": \"Deletion-mutant reporter assays with TSA and MAPK inhibitor treatment plus colony formation\",\n      \"pmids\": [\"15601862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of HDAC-independent C-terminal silencing unknown\", \"Direct Ras/MAPK target on ING1 not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed ING1 is subject to spatial and signaling regulation through ARF-driven nucleolar redistribution and phospho-dependent 14-3-3 cytoplasmic tethering that blocks its activity.\",\n      \"evidence\": \"Co-IP, phosphatase treatment, subcellular fractionation, ARF-knockout MEFs, and p21WAF1 readouts\",\n      \"pmids\": [\"16581770\", \"16607280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase generating the 14-3-3 site not defined here\", \"Functional relationship of ARF and 14-3-3 control unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established phosphorylation- and genotype-dependent control of ING1, defining Ser-126 phosphorylation as a stability switch and demonstrating both p53-dependent senescence and p53-independent tumor suppression in vivo.\",\n      \"evidence\": \"In vitro kinase assays (Chk1/Cdk1), Ser126Ala mutagenesis with half-life measurement, and Ing1-knockout mice and MEFs\",\n      \"pmids\": [\"17585055\", \"17693408\", \"17332334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector pathway for p53-independent suppression incompletely defined\", \"Mechanism connecting Ser-126 to stability not molecularly resolved at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the structural and trafficking framework for ING1 function, defining the PHD finger as an H3K4me3 reader and establishing lamin-A-, karyopherin-, and NQO1-dependent localization and stability control.\",\n      \"evidence\": \"X-ray crystallography with mutagenesis, peptide microarray, LMNA-knockout cells, NLS mutagenesis, and in vitro proteasomal degradation assays\",\n      \"pmids\": [\"18533182\", \"18836436\", \"18655775\", \"18388957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H3K4me3 reading is coupled to complex recruitment in vivo not fully defined\", \"Hierarchy among localization controls unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified chromatin-level transcriptional targets of ING1 (DGCR8) genome-wide, connecting its chromatin function to proliferation control.\",\n      \"evidence\": \"Expression microarray in Ing1-null MEFs, ChIP at the DGCR8 promoter, and proliferation assays\",\n      \"pmids\": [\"20179197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation of broader target set unclear\", \"Chromatin complex used at DGCR8 not specified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the molecular basis of ING1-mediated p53 stabilization and its role in p16INK4a-driven senescence, linking ubiquitin binding and HAUSP recruitment to tumor-suppressor output.\",\n      \"evidence\": \"Ubiquitin-binding/Kd measurements, ING1-HAUSP Co-IP, p53 ubiquitination assays, and p16 ChIP with curcumin inhibition\",\n      \"pmids\": [\"21731648\", \"21896275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HAUSP recruitment is constitutive or signal-induced not defined\", \"Single lab for both findings\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Broadened ING1 mechanism to DNA demethylation targeting, p53-independent mitochondrial apoptosis via BAX, and Src-driven cytoplasmic relocalization, defining cytoplasmic and chromatin axes beyond p53.\",\n      \"evidence\": \"Xenopus Ing1 knockdown with methylation/ChIP analysis, ING1-BAX Co-IP with mitochondria-targeted constructs, and Src in vitro kinase plus Co-IP and apoptosis assays\",\n      \"pmids\": [\"23388825\", \"24008732\", \"23585863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BH3-like domain function not structurally validated\", \"Relationship between nuclear and mitochondrial pools unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established ING1 as a direct repressor of rRNA transcription, linking it to ribosome biogenesis control via HDAC1/NoRC recruitment and mTOR antagonism at the nucleolus.\",\n      \"evidence\": \"ChIP of ING1/HDAC1/NoRC at rDNA, Co-IP, rRNA quantification, and mTOR localization imaging with knockdown\",\n      \"pmids\": [\"27903908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ING1-mTOR/UBF antagonism not biochemically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ING1 mediates androgen-receptor-dependent repression of hTERT, extending its repressive chromatin role to hormone-regulated transcription.\",\n      \"evidence\": \"ChIP at the hTERT nARE, reporter assays, siRNA knockdown, and ex vivo patient samples\",\n      \"pmids\": [\"34439179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ING1 reads a specific chromatin mark at the nARE not defined\", \"Functional redundancy with ING2 unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the single H3K4me3-reading PHD finger is dynamically switched between activating HAT and repressive HDAC complexes, and how nuclear, nucleolar, and mitochondrial pools are coordinated during the damage response, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ING1 within an intact HAT or HDAC complex\", \"Determinants of complex selection in vivo unknown\", \"Quantitative coordination of subcellular pools during apoptosis not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [21, 26, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 13, 15, 33, 37]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 13, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [27, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 23, 22]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [9, 17, 29, 33]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 32]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [26, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 11, 12, 13, 33]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 15, 25, 37]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 8, 31]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10, 21, 30]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 19, 26]}\n    ],\n    \"complexes\": [\n      \"Sin3-HDAC1 (mSin3A/SAP30/RbAp48)\",\n      \"NuA4 HAT complex\",\n      \"NoRC\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"PCNA\",\n      \"SAP30\",\n      \"HDAC1\",\n      \"LMNA\",\n      \"BAX\",\n      \"USP7/HAUSP\",\n      \"GADD45A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}