{"gene":"CITED2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2003,"finding":"CITED2 transactivation domain (TAD) binds the CH1 domain of p300/CBP with high affinity and displaces the HIF-1α C-terminal TAD from a partially overlapping binding surface; a conserved LPEL motif in CITED2 is critical for this interaction, and mutation of LPEL abolishes p300 binding in vivo. High-resolution NMR solution structure of the CITED2 TAD–p300 CH1 complex was determined.","method":"NMR structure determination, in vitro binding assay, site-directed mutagenesis of LPEL motif, in vivo co-immunoprecipitation","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 — crystal/NMR structure with mutagenesis and in vivo validation in single rigorous study","pmids":["12778114"],"is_preprint":false},{"year":2003,"finding":"NMR structure of CBP TAZ1 bound to CITED2 activation domain reveals that CITED2 is intrinsically disordered and folds upon binding, forming an α-helix (αA) and extended structure that wraps around TAZ1. CITED2 and HIF-1α use partly overlapping but non-identical surfaces on TAZ1 (both contain an LP(E/Q)L motif binding the same TAZ1 junction) to compete for CBP, with CITED2 binding the αA/α1/α4 interface not used by HIF-1α.","method":"NMR structure determination, binding studies, structural comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — high-resolution NMR structure with detailed mechanistic analysis, independent from PMID 12778114","pmids":["14594809"],"is_preprint":false},{"year":2001,"finding":"CITED2 physically interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2−/− embryonic fibroblasts and is rescued by ectopically expressed CITED2. Cited2−/− embryos die with cardiac malformations, adrenal agenesis, neural crest defects, and exencephaly.","method":"Co-immunoprecipitation, transient transfection reporter assay, Cited2 knockout mouse analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus functional rescue plus in vivo knockout phenotype; highly cited foundational paper","pmids":["11694877"],"is_preprint":false},{"year":2003,"finding":"p300, TFAP2A, and endogenous CITED2 form a physical ternary complex in vivo; p300 co-activates TFAP2A only in the presence of CITED2, and this requires the histone acetyltransferase activity of p300. CITED2 interacts with the dimerization domain of TFAP2C/A. Full-length p300 and TFAP2A interact in mammalian two-hybrid assays only when CITED2 is co-transfected.","method":"Co-immunoprecipitation from transfected U2-OS cells, mammalian two-hybrid assay, HAT-deficient p300 mutant (D1399Y), transient transfection reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, two-hybrid, and functional mutagenesis with multiple orthogonal methods","pmids":["12586840"],"is_preprint":false},{"year":2002,"finding":"CITED2 acts as a negative regulator of HIF-1α by competing for binding to CBP/p300. Loss of Cited2 leads to elevated HIF-1α-responsive gene expression (VEGF, Glut1, PGK1) in embryonic hearts and cultured fibroblasts under hypoxia, establishing Cited2 as an in vivo inhibitor of HIF-1 transcriptional activity.","method":"Cited2 knockout mouse, quantitative RT-PCR of HIF-1α target genes, hypoxia cell culture experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean knockout with specific molecular readout, replicated in multiple papers","pmids":["12149478"],"is_preprint":false},{"year":2004,"finding":"CITED2 and TFAP2 activate Pitx2c transcription at its promoter, and CITED2-null mice lack Nodal target gene expression (Pitx2c, Nodal, Ebaf) in the left lateral plate mesoderm, placing CITED2 upstream of a Nodal→Pitx2c pathway for left-right axis determination. CITED2 and TFAP2 were detected at the Pitx2c promoter by ChIP in embryonic hearts.","method":"Cited2 knockout mouse, in situ hybridization, chromatin immunoprecipitation (ChIP), transient transfection reporter assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus genetic epistasis plus reporter assay, replicated in subsequent papers","pmids":["15475956"],"is_preprint":false},{"year":2007,"finding":"CITED2 interacts with WT1 to co-activate expression of SF-1 (Nr5a1) in the adrenogonadal primordium above the threshold required for adrenal development. Genetic and molecular evidence shows that Cited2 and Wt1 act in the same pathway to regulate Sf-1 dosage during adrenal cortex specification.","method":"Mouse genetics (Cited2/Wt1/Sf-1 compound mutants), gene expression analysis, genetic epistasis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple compound mutant backgrounds, direct correlation between Sf-1 levels and phenotype severity","pmids":["17537799"],"is_preprint":false},{"year":2007,"finding":"FOXO3a induces transcription of CITED2 during hypoxia in a HIF1-dependent manner. CITED2 then reduces HIF1 activity (negative feedback), limiting expression of proapoptotic HIF1 targets NIX and RTP801. FOXO3a inhibits HIF1-induced apoptosis via CITED2.","method":"Reporter assay, loss-of-function studies in fibroblasts and breast cancer cells, gene expression analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple cell types with loss-of-function and defined molecular epistasis","pmids":["18158893"],"is_preprint":false},{"year":2012,"finding":"CITED2 inhibits acetylation of PGC-1α by blocking its interaction with the acetyltransferase GCN5, thereby enhancing PGC-1α transcriptional coactivation activity and increasing gluconeogenic gene expression. Insulin disrupts CITED2–GCN5 interaction via PI3K-Akt signaling. CITED2 abundance in liver is increased by glucagon-cAMP-PKA signaling during fasting.","method":"Co-immunoprecipitation, loss-of-function mouse model, reporter assay, gene expression analysis, pharmacological inhibition of PI3K-Akt","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — co-IP, genetic KO, defined kinase pathway, multiple orthogonal methods in single study","pmids":["22426420"],"is_preprint":false},{"year":2016,"finding":"During fasting, PKA phosphorylates GCN5 in a CITED2-dependent manner, increasing GCN5 histone acetyltransferase (HAT) activity while attenuating PGC-1α acetylation. This substrate switch simultaneously promotes epigenetic activation of gluconeogenic gene promoters and PGC-1α-mediated coactivation, constituting a GCN5-CITED2-PKA signaling module.","method":"In vitro kinase assay, co-immunoprecipitation, HAT activity assay, mouse genetic models, gene expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of PKA phosphorylation of GCN5, HAT activity assay, complemented by genetic mouse models","pmids":["27874008"],"is_preprint":false},{"year":2009,"finding":"Conditional deletion of Cited2 in adult mice causes selective, cell-autonomous loss of hematopoietic stem cells (HSCs), leading to multilineage bone marrow failure. Concurrent deletion of Ink4a/Arf or Trp53 restores HSC functionality, placing CITED2 upstream of Ink4a/Arf and p53 in HSC maintenance.","method":"Conditional Cre-mediated knockout, bone marrow transplantation, genetic epistasis with Ink4a/Arf and Trp53 deletion","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with cell-autonomous rescue by genetic epistasis, multiple lineage analyses","pmids":["19951693"],"is_preprint":false},{"year":2006,"finding":"CITED2 interacts physically with Smad2 and Smad3 (supported by co-IP, mammalian two-hybrid, and GST pulldown). p300 enhances CITED2-Smad3 interaction. CITED2 is recruited with Smad3 to the MMP9 promoter upon TGF-β stimulation and enhances TGF-β-mediated MMP9 upregulation and cell invasion.","method":"Co-immunoprecipitation, mammalian two-hybrid, GST pulldown, chromatin immunoprecipitation, luciferase reporter assay, invasion assay with siRNA knockdown","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — three independent binding assays plus ChIP and functional knockdown","pmids":["16619037"],"is_preprint":false},{"year":2007,"finding":"Cited2 is a coactivator of HNF4α; physical interaction was demonstrated by co-IP. ChIP confirmed CITED2 is recruited to HNF4α-responsive promoters. Loss of Cited2 reduces HNF4α binding to target gene promoters in fetal liver, resulting in liver hypoplasia.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, Cited2 knockout mouse liver analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus ChIP plus genetic KO with defined molecular phenotype","pmids":["17932483"],"is_preprint":false},{"year":2004,"finding":"CITED2 was identified as a direct PPARα-interacting protein; it binds predominantly via the ligand-binding domain of PPARα and acts as a dose-dependent coactivator of PPARα-dependent transcriptional regulation in reporter assays, independently of ligand.","method":"cDNA library interaction cloning with bacterially expressed PPARα, co-immunoprecipitation, transient transfection reporter assay, stable overexpression/siRNA knockdown cell lines, microarray","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — interaction cloning plus reporter assay, single lab","pmids":["15051727"],"is_preprint":false},{"year":2003,"finding":"CITED2 overexpression in Cited2−/− fibroblasts induces Bmi1 and Mel18 (polycomb-group genes) and decreases Ink4a/ARF expression, rescuing premature proliferation arrest. Deletion of Ink4a/ARF rescues defective proliferation of Cited2−/− fibroblasts. Bmi1 and Mel18 retroviruses rescue proliferation, placing them downstream of CITED2.","method":"Retroviral complementation, Ink4a/ARF genetic deletion in Cited2−/− background, gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple compound mutants and retroviral rescue","pmids":["14560011"],"is_preprint":false},{"year":2010,"finding":"CITED2 competes with MMP transactivator Ets-1 for binding to p300, thereby suppressing MMP-1 expression. Moderate flow shear (5 dyn/cm²) induces CITED2 via a TGF-β-dependent pathway, dissociates Ets-1 from p300, and associates CITED2 with p300. CITED2 induction requires p38δ phosphorylation.","method":"Competitive binding assay, transcription reporter assay, co-immunoprecipitation, antisense/sense CITED2 transfection, p38δ pharmacological inhibition","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — competitive binding assay plus co-IP plus functional reporter assay, in vitro and in vivo components","pmids":["20826544"],"is_preprint":false},{"year":2003,"finding":"CITED2 is induced by fluid shear stress and suppresses MMP-1 and MMP-13 expression in chondrocytes. Overexpression represses MMP-1/MMP-13, antisense CITED2 prevents shear-induced downregulation. CITED2 associates with p300, displacing Ets-1 from p300, in a TGF-β-dependent manner.","method":"Sense/antisense CITED2 transfection, co-immunoprecipitation, MMP activity assay, flow shear cell culture system","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function with molecular mechanism via co-IP","pmids":["12960175"],"is_preprint":false},{"year":2010,"finding":"CITED2 constitutively localizes in the nucleus and interacts with p300, preventing p65 from binding to p300, impairing p65 acetylation, and reducing p65 binding to NF-κB-responsive promoters. LPS induces CITED2 expression via NF-κB, establishing a negative feedback loop. CITED2 sensitizes cells to TNF-α-induced apoptosis.","method":"Co-immunoprecipitation, ChIP, reporter assay, siRNA knockdown, CITED2 overexpression, LPS stimulation of macrophages","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — co-IP, ChIP, and gain/loss-of-function with defined molecular mechanism","pmids":["21098220"],"is_preprint":false},{"year":2011,"finding":"CITED2 inactivates HIF-1α N-terminal transactivation domain (NAD) activity by interfering with NAD binding to the CH1 domain of p300, while also blocking C-terminal TAD-p300 interaction; NAD interacts with both CH1 and CH3 domains of p300, but CITED2 only blocks CH1 binding.","method":"Co-immunoprecipitation, reporter assay for NAD- and CAD-dependent genes, domain mapping","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and reporter assay, single lab","pmids":["21925214"],"is_preprint":false},{"year":2007,"finding":"CITED2 is degraded via the ubiquitin-proteasome pathway; proteasome inhibition (MG132) stabilizes CITED2 protein, which then inactivates HIF-1 by blocking HIF-1α-p300 interaction, explaining the paradoxical reduction of HIF-1 activity despite HIF-1α protein accumulation upon proteasome inhibition.","method":"Proteasome inhibitor MG132 treatment, CITED2 siRNA knockdown, reporter assay, Western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function rescue with defined molecular pathway, single lab","pmids":["17906695"],"is_preprint":false},{"year":2015,"finding":"FBXL5 directly interacts with CITED2 and promotes its proteasome-dependent degradation; FBXL5 depletion increases CITED2 protein levels, whereas FBXL5 overexpression decreases them. FBXL5-mediated CITED2 degradation impairs CITED2-CH1(p300) interaction and enables HIF-1α N-terminal TAD transcriptional activity.","method":"Co-immunoprecipitation, RNA interference, overexpression, reporter assay, mouse embryonic stem cells","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP and RNAi with functional reporter, single lab","pmids":["25956243"],"is_preprint":false},{"year":2012,"finding":"CITED2 interacts with MYC and recruits p300 to promote MYC-p300-mediated transactivation of E2F3, driving G1/S cell cycle progression. CITED2 also interacts with HDAC1 and potentiates MYC-HDAC1 complex formation to suppress p21CIP1, inhibiting cellular quiescence.","method":"Co-immunoprecipitation, reporter assay, ChIP, siRNA knockdown, gain-of-function experiments","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and ChIP plus functional phenotypic readouts, single lab","pmids":["22814619"],"is_preprint":false},{"year":2012,"finding":"HIF-1α deletion partially rescues impaired HSC quiescence and reconstitution capacity caused by Cited2 deficiency, and restores p57 and Hes1 (but not Egr1) expression, indicating that CITED2 regulates HSC quiescence via both HIF-1-dependent and HIF-1-independent pathways.","method":"Conditional double-knockout mouse (Cited2/HIF-1α), flow cytometry, bone marrow transplantation, gene expression profiling","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with double-KO and defined molecular readouts","pmids":["22308296"],"is_preprint":false},{"year":2006,"finding":"HIF-1α haploinsufficiency largely rescues outflow tract, interventricular septal, cardiac vascular, and hyposplenia defects in Cited2−/− embryos, and reduces HIF-1α-responsive gene mRNA levels in these hearts, providing in vivo evidence that CITED2 regulates cardiac development through inhibition of HIF-1 transcriptional activity.","method":"Cited2/HIF-1α compound mutant mouse, cardiac histology, MRI, gene expression analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic rescue with HIF-1α haploinsufficiency, replicated in subsequent studies","pmids":["17022961"],"is_preprint":false},{"year":2012,"finding":"CITED2 is recruited to the Oct4 promoter during early ESC differentiation to regulate Oct4 expression; loss of Cited2 delays silencing of pluripotency genes (Oct4, Klf4, Sox2, c-Myc) and impairs cardiomyocyte, hematopoietic, and neuronal differentiation.","method":"ChIP, gene knockout ESCs, qRT-PCR, differentiation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus genetic KO with differentiation phenotype, single lab","pmids":["22761414"],"is_preprint":false},{"year":2015,"finding":"Cited2 directly targets Nanog, Tbx3, and Klf4 in ESCs; acute loss of Cited2 reduces Nanog expression and ESC self-renewal, and this is rescued by constitutive Nanog expression. Cited2 is also required for efficient reprogramming of fibroblasts to iPSCs.","method":"Inducible Cre-mediated acute deletion, ChIP, rescue by Nanog overexpression, reprogramming assay","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus genetic rescue with defined molecular targets, single lab","pmids":["25377420"],"is_preprint":false},{"year":2009,"finding":"CITED2 interacts with WT1 and SF1 to promote Sry expression in the XY gonad above the threshold required for testis determination; reducing Wt1 or Sf1 dosage in Cited2 mutants produces XY sex reversal, defining Sry as a downstream target of the CITED2/WT1/SF1 regulatory pathway.","method":"Compound mutant mouse genetics, gene expression analysis, genetic epistasis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multi-allele genetic epistasis in vivo with quantitative expression correlates","pmids":["19457926"],"is_preprint":false},{"year":2012,"finding":"CITED2 acts as a molecular chaperone guiding PRMT5 and p300 to nucleolin, thereby activating nucleolin and promoting epithelial-mesenchymal transition and prostate cancer metastasis.","method":"Co-immunoprecipitation, siRNA knockdown, xenograft mouse model, migration/invasion assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP with functional cellular phenotype, single lab","pmids":["30291252"],"is_preprint":false},{"year":2010,"finding":"Loss of Cited2 from heart progenitors (using cardiac-specific Cre) does not alter development; heart defects in Cited2-null embryos arise from an extra-cardiac requirement for Cited2 in establishing the left-right body axis. Cited2 also acts as a potentiator of BMP signaling to counteract Nodal initiation in the left lateral plate mesoderm.","method":"Conditional cardiac-specific knockout, molecular genetic analysis, gene expression studies","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — conditional lineage-specific deletion dissecting cell-autonomous vs. non-autonomous requirement","pmids":["21224256"],"is_preprint":false},{"year":2008,"finding":"Deletion of HIF-1α specifically in Cited2−/− lens eliminates excessive hyaloid vasculature hypercellularity without affecting the corneal-lenticular stalk phenotype; increased Pax6 dosage rescues the lens morphogenesis defect. This dissects two distinct CITED2 functions: one through HIF-1 in hyaloid vascular formation, and another upstream of or together with Pax6 in lens morphogenesis.","method":"Conditional double-knockout (lens-specific HIF-1α deletion in Cited2−/− background), Pax6 rescue genetics","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — double conditional KO dissecting two independent pathways with specific molecular rescue","pmids":["18653562"],"is_preprint":false},{"year":2012,"finding":"CITED2 is a direct effector of PPARγ; PPARγ binds the CITED2 promoter by ChIP, and PPARγ activation induces CITED2 expression in HCC cells. CITED2 knockdown increases cell viability and promotes G1-S transition; CITED2 overexpression suppresses HCC cell growth and upregulates CDK inhibitors p15, p21, p27.","method":"ChIP-PCR, adenovirus-PPARγ transduction, siRNA knockdown, gain-of-function proliferation assay","journal":"Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus gain/loss-of-function, single lab","pmids":["23212831"],"is_preprint":false},{"year":2016,"finding":"CITED2 is recruited to the IKKα promoter (by ChIP) and directly regulates IKKα expression; CITED2 knockdown reduces IKKα, inhibits both canonical and noncanonical NF-κB signaling, and impairs breast cancer cell invasion. IKKα re-expression in CITED2-knockdown cells rescues invasive ability.","method":"ChIP, siRNA knockdown, IKKα rescue experiment, NF-κB reporter assay, invasion assay, xenograft","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus rescue experiment with defined molecular epistasis, single lab","pmids":["27216153"],"is_preprint":false},{"year":2011,"finding":"CITED2 knockdown induces CBP/p300-mediated p53 acetylation at Lys373, reduces p53 ubiquitination, and stabilizes p53 protein, sensitizing cancer cells to cisplatin-induced apoptosis.","method":"shRNA knockdown, Western blot for p53 acetylation and ubiquitination, cisplatin sensitivity assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, loss-of-function with defined PTM readout but no direct interaction assay for CITED2-p300-p53","pmids":["21660965"],"is_preprint":false},{"year":2008,"finding":"CITED2 signals through PPARγ to promote neuronal death after DNA damage; CITED2 upregulation is downstream of Cdk4 but upstream of the mitochondrial apoptotic pathway and independent of p53. CITED2 overexpression promotes cortical neuron death; CITED2 deficiency protects.","method":"Gene array, retroviral overexpression, CITED2 knockout neurons, Cdk4 inhibition, camptothecin DNA damage model","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — gain and loss-of-function with genetic epistasis placing CITED2 downstream of Cdk4 and upstream of mitochondrial apoptosis","pmids":["18495890"],"is_preprint":false},{"year":2012,"finding":"Cited2 is required for maintenance of glycolytic metabolism in adult HSCs; Cited2 deficiency reduces Pdk2, Pdk4, LDHB, and LDHD expression, increases mitochondrial activity and ROS, and elevated Akt/mTORC1 signaling. PI3K-Akt inhibition (but not mTORC1 inhibition alone) partially rescues Pdk4 repression.","method":"Conditional Cited2 knockout, metabolic assays (glycolysis, mitochondrial activity, ROS, ATP), gene expression, pharmacological rescue with PI3K and mTOR inhibitors","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with metabolic phenotyping and pharmacological rescue, single lab","pmids":["24083546"],"is_preprint":false},{"year":2006,"finding":"TGF-β downregulates Cited2 post-transcriptionally via the Smad pathway (Smad4-dependent, Smad7-inhibitable) by accelerating Cited2 mRNA turnover; this requires the C-terminal conserved region of the Cited2 coding sequence. Cited2 transcription is not affected by TGF-β.","method":"Nuclear run-on assay, Cited2 promoter reporter assay, Smad4 knockdown/Smad7 overexpression, mRNA stability assay with transcriptional inhibitors, deletion constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple complementary approaches distinguishing transcriptional from post-transcriptional regulation, single lab","pmids":["16675452"],"is_preprint":false},{"year":2016,"finding":"CITED2 is recruited to the Vegfa promoter in mouse embryonic hearts (by ChIP) and cooperates with TFAP2 to stimulate VEGFA promoter activity. Cardiomyocyte-specific Cited2 knockout results in compact layer thinning, reduced capillary density, and reduced Vegfa expression.","method":"Cardiomyocyte-specific conditional knockout, ChIP, transient transfection reporter assay, MRI, vessel morphometry","journal":"European heart journal","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with ChIP and reporter assay, multiple orthogonal methods","pmids":["22504313"],"is_preprint":false},{"year":2016,"finding":"CITED2 is required for optimal PPARγ activation and anti-inflammatory gene expression in macrophages; CITED2 deficiency stabilizes HIF-1α protein, heightening proinflammatory gene expression. Overexpression of Egln3 or HIF-1α inhibition reverses elevated inflammation in Cited2-deficient macrophages. Myeloid-specific Cited2 KO mice are highly susceptible to endotoxin-induced sepsis.","method":"Myeloid-specific conditional knockout, gain- and loss-of-function, HIF-1α protein stability assay, Egln3 overexpression rescue, PPARγ reporter assay, LPS sepsis model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with genetic rescue and defined molecular epistasis, in vivo disease model","pmids":["29203644"],"is_preprint":false},{"year":2021,"finding":"CITED2 deficiency in macrophages elevates IFNγ-induced STAT1 transcriptional activity, STAT1 enrichment on the IRF1 promoter, and IRF1-regulated pro-inflammatory gene expression. siRNA knockdown of IRF1 completely reverses elevated pro-inflammatory expression in CITED2-deficient macrophages. Myeloid CITED2-deficient mice on Apoe−/− background develop larger atherosclerotic lesions.","method":"Myeloid-specific conditional knockout, IRF1 siRNA rescue, ChIP for STAT1 at IRF1 promoter, atherosclerosis mouse model, transcriptomics/GSEA","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — ChIP, genetic rescue, in vivo atherosclerosis model, multiple orthogonal methods","pmids":["34365659"],"is_preprint":false},{"year":2013,"finding":"Indoxyl sulfate (uremic toxin) markedly upregulates CITED2 via post-transcriptional mRNA stabilization involving the ERK1/2 pathway. Elevated CITED2 impairs HIF-1α C-terminal transactivation domain (CTAD) function without altering HIF-1α protein levels, thereby suppressing hypoxia-inducible gene expression.","method":"Reporter assay for HIF-1α CTAD activity, qRT-PCR, ERK1/2 inhibition, mRNA stability experiments, in vivo CKD models","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — post-transcriptional mechanism with ERK inhibitor and reporter assay, in vivo validation, single lab","pmids":["23792300"],"is_preprint":false},{"year":2016,"finding":"CITED2 is recruited to the Cebpa promoter in embryonic lung (by ChIP) in cooperation with Tcfap2c to activate Cebpa transcription, which is required for alveolar epithelial cell differentiation and lung maturation.","method":"ChIP in E18.5 lungs, Cited2 knockout lung phenotype, gene expression analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus genetic KO with defined molecular target, single lab","pmids":["18358466"],"is_preprint":false},{"year":2014,"finding":"In sinusoidal trophoblast giant cells and syncytiotrophoblasts, CITED2 non-cell-autonomously patterns pericytes associated with embryonic capillaries, likely via PDGF signaling. Loss of CITED2 in syncytiotrophoblasts causes subcellular mislocalization of the lactate transporter SLC16A3 (MCT4).","method":"Conditional trophoblast-specific Cre deletion, histology, immunofluorescence for MCT4 localization, PDGF signaling analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with specific subcellular localization phenotype and proposed signaling mechanism, single lab","pmids":["24803182"],"is_preprint":false},{"year":2020,"finding":"Computational structure-based modeling of TAZ1-CITED2-HIF-1α ternary system reveals that CITED2 forms the thermodynamically lowest energy complex with TAZ1 and binds TAZ1 faster kinetically than HIF-1α, explaining CITED2's superior competitive displacement of HIF-1α from p300.","method":"Structure-based computational modeling, free energy surface analysis, kinetic simulations","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 4 — computational only, no in vitro experimental validation in this paper","pmids":["32123067"],"is_preprint":false},{"year":2021,"finding":"A constrained (helix-stabilized) peptide derived from the CITED2 transactivation domain potently inhibits the HIF-1α–p300 interaction with high biochemical affinity, cell penetration, and serum stability, establishing that the CITED2-derived LPEL-containing helix is a pharmacologically tractable competitive inhibitor scaffold.","method":"In vitro binding affinity assay, cell penetration assay, serum stability assay, HIF-1α/p300 competition assay","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstituted competitive binding with constrained peptide, single study","pmids":["34472840"],"is_preprint":false}],"current_model":"CITED2 is a nuclear transcriptional co-regulator that lacks intrinsic DNA-binding activity and functions primarily by binding with high affinity to the CH1 (TAZ1) domain of p300/CBP, thereby competing with HIF-1α (and other transcription factors) for co-activator recruitment; it co-activates TFAP2, HNF4α, PPARα/γ, SF-1 (via WT1), ISL1, Smad3, and estrogen receptor through p300/CBP bridging, while negatively regulating HIF-1α, NF-κB-p65, and STAT1-IRF1 by blocking their access to p300, and modulates gluconeogenesis by blocking GCN5-dependent PGC-1α acetylation in a glucagon-PKA-dependent manner."},"narrative":{"teleology":[{"year":2001,"claim":"The initial question was whether CITED2 had transcription factor partners beyond p300/CBP; the discovery that CITED2 physically interacts with and is required for TFAP2-dependent transactivation, combined with the severe Cited2-null phenotype, established it as a co-activator essential for cardiac, neural crest, and adrenal development.","evidence":"Co-IP, reporter assays, and Cited2 knockout mouse with lethal cardiac malformations and adrenal agenesis","pmids":["11694877"],"confidence":"High","gaps":["Structural basis of the CITED2–TFAP2 interface was not defined","Whether cardiac defects were cell-autonomous was unknown"]},{"year":2002,"claim":"This established the in vivo consequence of CITED2's competition with HIF-1α for p300/CBP: loss of Cited2 derepressed HIF-1 target genes in embryonic hearts and fibroblasts, confirming CITED2 as a physiological negative regulator of HIF-1 transcriptional activity.","evidence":"Cited2 knockout mouse with quantitative RT-PCR of HIF-1α target genes under hypoxia","pmids":["12149478"],"confidence":"High","gaps":["Mechanism of competitive displacement was structurally undefined at this point","Whether HIF-1 derepression caused the cardiac defects was untested"]},{"year":2003,"claim":"Two independent NMR structures resolved how CITED2's intrinsically disordered TAD folds upon binding to the TAZ1 (CH1) domain of p300/CBP and identified the conserved LPEL motif as the critical contact that overlaps with the HIF-1α binding surface, providing the atomic basis for competitive displacement.","evidence":"NMR solution structures of CITED2 TAD–p300 CH1 complex, mutagenesis of LPEL motif, in vivo co-IP","pmids":["12778114","14594809"],"confidence":"High","gaps":["Kinetic parameters of displacement were not measured experimentally","How CITED2 simultaneously co-activates TFAP2 while occupying the same CH1 domain was unclear"]},{"year":2003,"claim":"The ternary complex model was established: p300, TFAP2, and CITED2 form a physical complex in vivo, with CITED2 bridging TFAP2 to p300 in a HAT activity-dependent manner, resolving the question of how a co-activator lacking DNA-binding activity enhances transcription.","evidence":"Co-IP from U2-OS cells, mammalian two-hybrid, HAT-dead p300 mutant","pmids":["12586840"],"confidence":"High","gaps":["Whether this ternary model generalizes to other CITED2-dependent TF complexes was untested"]},{"year":2003,"claim":"CITED2 was placed upstream of polycomb-group gene regulation (Bmi1/Mel18) and Ink4a/ARF, explaining the premature senescence of Cited2-null fibroblasts and foreshadowing its role in stem cell maintenance.","evidence":"Retroviral complementation and Ink4a/ARF genetic deletion in Cited2−/− fibroblasts","pmids":["14560011"],"confidence":"High","gaps":["Direct transcriptional mechanism linking CITED2 to Bmi1/Mel18 was not defined","Whether the same pathway operates in HSCs was unknown"]},{"year":2004,"claim":"CITED2 and TFAP2 were shown to activate the Pitx2c promoter (by ChIP), placing CITED2 in the Nodal→Pitx2c left-right patterning pathway and explaining the laterality defects in Cited2-null embryos.","evidence":"ChIP in embryonic hearts, in situ hybridization in Cited2 knockout, reporter assay","pmids":["15475956"],"confidence":"High","gaps":["Whether CITED2 acts directly in the node or lateral plate mesoderm was unresolved"]},{"year":2006,"claim":"Multiple new co-activation partnerships and a post-transcriptional regulatory mechanism were defined: CITED2 co-activates Smad2/3 at the MMP9 promoter upon TGF-β stimulation, and TGF-β also downregulates Cited2 mRNA post-transcriptionally via Smad4-dependent mRNA destabilization, revealing a complex TGF-β–CITED2 regulatory circuit.","evidence":"Co-IP, GST pulldown, mammalian two-hybrid for Smad interaction; nuclear run-on and mRNA stability assays for post-transcriptional regulation","pmids":["16619037","16675452"],"confidence":"High","gaps":["The RNA element mediating Cited2 mRNA destabilization was mapped only to the C-terminal coding region"]},{"year":2006,"claim":"Genetic rescue of Cited2-null cardiac defects by HIF-1α haploinsufficiency provided definitive in vivo evidence that excess HIF-1 activity accounts for many of the cardiac malformations, validating the competitive displacement model at the organismal level.","evidence":"Cited2/HIF-1α compound mutant mouse with cardiac histology, MRI, and gene expression","pmids":["17022961"],"confidence":"High","gaps":["Not all phenotypes were rescued, indicating HIF-1-independent CITED2 functions in cardiac development"]},{"year":2007,"claim":"CITED2 was established as a critical co-activator of WT1 and SF-1 to regulate adrenal and gonadal development, with compound mutant analysis showing dosage-sensitive control of Sf-1 expression — and separately, HNF4α coactivation was defined in fetal liver, broadening the portfolio of CITED2's tissue-specific TF partnerships.","evidence":"Cited2/Wt1/Sf-1 compound mutant genetics; co-IP and ChIP for HNF4α in fetal liver with Cited2 KO","pmids":["17537799","17932483"],"confidence":"High","gaps":["Whether CITED2 directly bridges WT1 and p300 at Sf-1 promoters was not shown by ChIP"]},{"year":2007,"claim":"FOXO3a-mediated induction of CITED2 during hypoxia established a negative feedback loop limiting HIF-1 pro-apoptotic target gene expression, integrating CITED2 into the FOXO3a survival signaling network.","evidence":"Reporter assays and loss-of-function in fibroblasts and breast cancer cells","pmids":["18158893"],"confidence":"High","gaps":["Whether this loop operates in vivo in tumor hypoxia was not tested"]},{"year":2009,"claim":"Conditional deletion in adult mice revealed that CITED2 is essential cell-autonomously for HSC maintenance; concurrent Ink4a/Arf or Trp53 deletion rescued HSC function, connecting CITED2's earlier fibroblast senescence pathway to adult stem cell biology.","evidence":"Conditional Cre-mediated KO, bone marrow transplantation, genetic epistasis with Ink4a/Arf and Trp53","pmids":["19951693"],"confidence":"High","gaps":["Direct transcriptional targets of CITED2 in HSCs were not comprehensively identified","How CITED2 regulates p53 at the molecular level was unclear"]},{"year":2010,"claim":"CITED2's mechanism as a competitive inhibitor was extended to NF-κB signaling: nuclear CITED2 sequesters p300 from p65, impairing p65 acetylation and DNA binding, while LPS induces CITED2 via NF-κB itself, forming a negative feedback loop in macrophages.","evidence":"Co-IP, ChIP, reporter assay, siRNA knockdown and overexpression in LPS-stimulated macrophages","pmids":["21098220"],"confidence":"High","gaps":["Whether this mechanism accounts for CITED2's anti-inflammatory function in vivo was not tested at this point"]},{"year":2012,"claim":"A metabolic regulatory function was uncovered: CITED2 blocks GCN5-mediated PGC-1α acetylation to enhance gluconeogenic gene expression during fasting, with CITED2 abundance itself regulated by glucagon-cAMP-PKA signaling and opposed by insulin-PI3K-Akt signaling.","evidence":"Co-IP, mouse genetic model, reporter assays, pharmacological PI3K-Akt inhibition","pmids":["22426420"],"confidence":"High","gaps":["Whether CITED2 directly interacts with GCN5 or acts through an intermediary was not fully resolved"]},{"year":2012,"claim":"In HSCs, HIF-1α deletion partially but not completely rescued Cited2-deficiency phenotypes, genetically dissecting HIF-1-dependent (quiescence genes p57, Hes1) from HIF-1-independent (Egr1) functions of CITED2 in stem cell maintenance.","evidence":"Conditional double-knockout (Cited2/HIF-1α), flow cytometry, bone marrow transplantation","pmids":["22308296"],"confidence":"High","gaps":["Identity of the HIF-1-independent pathway mediating Egr1 regulation was unknown"]},{"year":2012,"claim":"CITED2 was shown to interact with MYC and recruit p300 to transactivate E2F3 for G1/S progression, while also potentiating MYC-HDAC1-mediated repression of p21, revealing dual co-activator and co-repressor roles in cell cycle control.","evidence":"Co-IP, ChIP, siRNA knockdown, reporter assay","pmids":["22814619"],"confidence":"Medium","gaps":["Whether CITED2-MYC interaction is direct or p300-mediated was not fully resolved","In vivo relevance for tumorigenesis was not demonstrated"]},{"year":2016,"claim":"The GCN5-CITED2-PKA module was further refined: PKA phosphorylates GCN5 in a CITED2-dependent manner, switching GCN5 substrate preference from PGC-1α to histones at gluconeogenic promoters, achieving simultaneous epigenetic activation and coactivator deacetylation.","evidence":"In vitro kinase assay, HAT activity assay, co-IP, mouse genetic models","pmids":["27874008"],"confidence":"High","gaps":["The phosphorylation site on GCN5 was not mapped","Whether this module operates in non-hepatic tissues was untested"]},{"year":2016,"claim":"Tissue-specific conditional knockouts clarified that CITED2's role in cardiac outflow tract patterning is extra-cardiac (acting via left-right axis), while cardiomyocyte-specific deletion revealed a separate, cell-autonomous requirement for CITED2–TFAP2 co-activation of Vegfa in myocardial vascularization.","evidence":"Cardiac-specific vs. cardiomyocyte-specific conditional KO, ChIP at Vegfa promoter, MRI, vessel morphometry","pmids":["21224256","22504313"],"confidence":"High","gaps":["Whether CITED2 regulates Vegfa independently of HIF-1α in cardiomyocytes was not addressed"]},{"year":2021,"claim":"CITED2 deficiency in macrophages was shown to elevate STAT1-IRF1 pro-inflammatory signaling by increasing STAT1 enrichment at the IRF1 promoter, with myeloid CITED2 deletion exacerbating atherosclerosis, demonstrating a new anti-inflammatory axis beyond NF-κB and HIF-1.","evidence":"Myeloid conditional KO on Apoe−/− background, ChIP for STAT1 at IRF1, IRF1 siRNA rescue, transcriptomics","pmids":["34365659"],"confidence":"High","gaps":["Whether CITED2 directly competes with STAT1 for p300 or acts through another mechanism was not determined","Relative contribution of HIF-1, NF-κB, and STAT1-IRF1 pathways to the atherosclerosis phenotype was not dissected"]},{"year":null,"claim":"Major unresolved questions include the full structural basis of how CITED2 simultaneously co-activates diverse transcription factors while competitively inhibiting others at the same p300 CH1 domain, the identity and regulation of E3 ligases beyond FBXL5 controlling CITED2 turnover, and whether the GCN5-CITED2-PKA gluconeogenic module operates in metabolic tissues beyond liver.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full ternary structure of CITED2–p300–any partner TF exists","CITED2 ubiquitination sites and comprehensive E3 ligase regulation remain incomplete","Comprehensive ChIP-seq/CUT&RUN genome-wide occupancy studies in primary tissues are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,4,5,8,11,12,17,21,26,36,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4,7,15,17,18,37]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6,8,9,27]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,5,11,17,24,25]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2,3,5,11,12,17,21,36,38]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,9,15,16,31,37]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,5,6,23,26,28,29,36,40]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,37,38]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,9,34]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,7,19,39]}],"complexes":["p300/CBP-CITED2-TFAP2 ternary complex","GCN5-CITED2-PKA signaling module"],"partners":["EP300","CREBBP","TFAP2A","HIF1A","WT1","SMAD3","HNF4A","KAT2A"],"other_free_text":[]},"mechanistic_narrative":"CITED2 is an intrinsically disordered nuclear transcriptional co-regulator that modulates gene expression by bridging sequence-specific transcription factors to the acetyltransferase p300/CBP and by competitively displacing other p300/CBP-dependent activators from the CH1 (TAZ1) domain. Its transactivation domain folds upon binding to TAZ1 via a conserved LPEL motif, occupying a partially overlapping surface used by HIF-1α to effect potent competitive inhibition of HIF-1-dependent transcription — a mechanism validated structurally, genetically, and in vivo across cardiac development, hematopoietic stem cell maintenance, macrophage inflammation, and lens morphogenesis [PMID:12778114, PMID:12149478, PMID:19951693, PMID:29203644]. Simultaneously, CITED2 acts as a positive co-activator by recruiting p300/CBP to TFAP2, HNF4α, Smad2/3, WT1/SF-1, and MYC at target promoters including Pitx2c, Vegfa, Sry, and E2F3, and it modulates hepatic gluconeogenesis by blocking GCN5-mediated PGC-1α acetylation in a PKA-dependent signaling module [PMID:12586840, PMID:15475956, PMID:17932483, PMID:22426420, PMID:22814619]. CITED2 also suppresses NF-κB-p65 and STAT1-IRF1 signaling by sequestering p300, establishing anti-inflammatory negative feedback loops in macrophages relevant to endotoxemia and atherosclerosis [PMID:21098220, PMID:34365659]."},"prefetch_data":{"uniprot":{"accession":"Q99967","full_name":"Cbp/p300-interacting transactivator 2","aliases":["MSG-related protein 1","MRG-1","P35srj"],"length_aa":270,"mass_kda":28.5,"function":"Transcriptional coactivator of the p300/CBP-mediated transcription complex. Acts as a bridge, linking TFAP2 transcription factors and the p300/CBP transcriptional coactivator complex in order to stimulate TFAP2-mediated transcriptional activation. Positively regulates TGF-beta signaling through its association with the SMAD/p300/CBP-mediated transcriptional coactivator complex. Stimulates the peroxisome proliferator-activated receptors PPARA transcriptional activity. Enhances estrogen-dependent transactivation mediated by estrogen receptors. Also acts as a transcriptional corepressor; interferes with the binding of the transcription factors HIF1A or STAT2 and the p300/CBP transcriptional coactivator complex. Participates in sex determination and early gonad development by stimulating transcription activation of SRY. Plays a role in controlling left-right patterning during embryogenesis; potentiates transcriptional activation of NODAL-mediated gene transcription in the left lateral plate mesoderm (LPM). Plays an essential role in differentiation of the adrenal cortex from the adrenogonadal primordium (AGP); stimulates WT1-mediated transcription activation thereby up-regulating the nuclear hormone receptor NR5A1 promoter activity. Associates with chromatin to the PITX2 P1 promoter region","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q99967/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CITED2","classification":"Not Classified","n_dependent_lines":107,"n_total_lines":1208,"dependency_fraction":0.08857615894039735},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CITED2","total_profiled":1310},"omim":[{"mim_id":"614433","title":"ATRIAL SEPTAL DEFECT 8; ASD8","url":"https://www.omim.org/entry/614433"},{"mim_id":"614431","title":"VENTRICULAR SEPTAL DEFECT 2; VSD2","url":"https://www.omim.org/entry/614431"},{"mim_id":"614429","title":"VENTRICULAR SEPTAL DEFECT 1; VSD1","url":"https://www.omim.org/entry/614429"},{"mim_id":"608232","title":"LEUKEMIA, CHRONIC MYELOID; CML","url":"https://www.omim.org/entry/608232"},{"mim_id":"606815","title":"CBP/P300-INTERACTING TRANSACTIVATOR, WITH GLU/ASP-RICH CARBOXY TERMINAL DOMAIN, 4; CITED4","url":"https://www.omim.org/entry/606815"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CITED2"},"hgnc":{"alias_symbol":["MRG1"],"prev_symbol":[]},"alphafold":{"accession":"Q99967","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99967","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99967-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99967-F1-predicted_aligned_error_v6.png","plddt_mean":51.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CITED2","jax_strain_url":"https://www.jax.org/strain/search?query=CITED2"},"sequence":{"accession":"Q99967","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99967.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99967/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99967"}},"corpus_meta":[{"pmid":"11694877","id":"PMC_11694877","title":"Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 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High-resolution NMR solution structure of the CITED2 TAD–p300 CH1 complex was determined.\",\n      \"method\": \"NMR structure determination, in vitro binding assay, site-directed mutagenesis of LPEL motif, in vivo co-immunoprecipitation\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal/NMR structure with mutagenesis and in vivo validation in single rigorous study\",\n      \"pmids\": [\"12778114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NMR structure of CBP TAZ1 bound to CITED2 activation domain reveals that CITED2 is intrinsically disordered and folds upon binding, forming an α-helix (αA) and extended structure that wraps around TAZ1. CITED2 and HIF-1α use partly overlapping but non-identical surfaces on TAZ1 (both contain an LP(E/Q)L motif binding the same TAZ1 junction) to compete for CBP, with CITED2 binding the αA/α1/α4 interface not used by HIF-1α.\",\n      \"method\": \"NMR structure determination, binding studies, structural comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution NMR structure with detailed mechanistic analysis, independent from PMID 12778114\",\n      \"pmids\": [\"14594809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CITED2 physically interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2−/− embryonic fibroblasts and is rescued by ectopically expressed CITED2. Cited2−/− embryos die with cardiac malformations, adrenal agenesis, neural crest defects, and exencephaly.\",\n      \"method\": \"Co-immunoprecipitation, transient transfection reporter assay, Cited2 knockout mouse analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional rescue plus in vivo knockout phenotype; highly cited foundational paper\",\n      \"pmids\": [\"11694877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p300, TFAP2A, and endogenous CITED2 form a physical ternary complex in vivo; p300 co-activates TFAP2A only in the presence of CITED2, and this requires the histone acetyltransferase activity of p300. CITED2 interacts with the dimerization domain of TFAP2C/A. Full-length p300 and TFAP2A interact in mammalian two-hybrid assays only when CITED2 is co-transfected.\",\n      \"method\": \"Co-immunoprecipitation from transfected U2-OS cells, mammalian two-hybrid assay, HAT-deficient p300 mutant (D1399Y), transient transfection reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, two-hybrid, and functional mutagenesis with multiple orthogonal methods\",\n      \"pmids\": [\"12586840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CITED2 acts as a negative regulator of HIF-1α by competing for binding to CBP/p300. Loss of Cited2 leads to elevated HIF-1α-responsive gene expression (VEGF, Glut1, PGK1) in embryonic hearts and cultured fibroblasts under hypoxia, establishing Cited2 as an in vivo inhibitor of HIF-1 transcriptional activity.\",\n      \"method\": \"Cited2 knockout mouse, quantitative RT-PCR of HIF-1α target genes, hypoxia cell culture experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockout with specific molecular readout, replicated in multiple papers\",\n      \"pmids\": [\"12149478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CITED2 and TFAP2 activate Pitx2c transcription at its promoter, and CITED2-null mice lack Nodal target gene expression (Pitx2c, Nodal, Ebaf) in the left lateral plate mesoderm, placing CITED2 upstream of a Nodal→Pitx2c pathway for left-right axis determination. CITED2 and TFAP2 were detected at the Pitx2c promoter by ChIP in embryonic hearts.\",\n      \"method\": \"Cited2 knockout mouse, in situ hybridization, chromatin immunoprecipitation (ChIP), transient transfection reporter assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus genetic epistasis plus reporter assay, replicated in subsequent papers\",\n      \"pmids\": [\"15475956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CITED2 interacts with WT1 to co-activate expression of SF-1 (Nr5a1) in the adrenogonadal primordium above the threshold required for adrenal development. Genetic and molecular evidence shows that Cited2 and Wt1 act in the same pathway to regulate Sf-1 dosage during adrenal cortex specification.\",\n      \"method\": \"Mouse genetics (Cited2/Wt1/Sf-1 compound mutants), gene expression analysis, genetic epistasis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple compound mutant backgrounds, direct correlation between Sf-1 levels and phenotype severity\",\n      \"pmids\": [\"17537799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FOXO3a induces transcription of CITED2 during hypoxia in a HIF1-dependent manner. CITED2 then reduces HIF1 activity (negative feedback), limiting expression of proapoptotic HIF1 targets NIX and RTP801. FOXO3a inhibits HIF1-induced apoptosis via CITED2.\",\n      \"method\": \"Reporter assay, loss-of-function studies in fibroblasts and breast cancer cells, gene expression analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types with loss-of-function and defined molecular epistasis\",\n      \"pmids\": [\"18158893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 inhibits acetylation of PGC-1α by blocking its interaction with the acetyltransferase GCN5, thereby enhancing PGC-1α transcriptional coactivation activity and increasing gluconeogenic gene expression. Insulin disrupts CITED2–GCN5 interaction via PI3K-Akt signaling. CITED2 abundance in liver is increased by glucagon-cAMP-PKA signaling during fasting.\",\n      \"method\": \"Co-immunoprecipitation, loss-of-function mouse model, reporter assay, gene expression analysis, pharmacological inhibition of PI3K-Akt\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, genetic KO, defined kinase pathway, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22426420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"During fasting, PKA phosphorylates GCN5 in a CITED2-dependent manner, increasing GCN5 histone acetyltransferase (HAT) activity while attenuating PGC-1α acetylation. This substrate switch simultaneously promotes epigenetic activation of gluconeogenic gene promoters and PGC-1α-mediated coactivation, constituting a GCN5-CITED2-PKA signaling module.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, HAT activity assay, mouse genetic models, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of PKA phosphorylation of GCN5, HAT activity assay, complemented by genetic mouse models\",\n      \"pmids\": [\"27874008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Conditional deletion of Cited2 in adult mice causes selective, cell-autonomous loss of hematopoietic stem cells (HSCs), leading to multilineage bone marrow failure. Concurrent deletion of Ink4a/Arf or Trp53 restores HSC functionality, placing CITED2 upstream of Ink4a/Arf and p53 in HSC maintenance.\",\n      \"method\": \"Conditional Cre-mediated knockout, bone marrow transplantation, genetic epistasis with Ink4a/Arf and Trp53 deletion\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with cell-autonomous rescue by genetic epistasis, multiple lineage analyses\",\n      \"pmids\": [\"19951693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CITED2 interacts physically with Smad2 and Smad3 (supported by co-IP, mammalian two-hybrid, and GST pulldown). p300 enhances CITED2-Smad3 interaction. CITED2 is recruited with Smad3 to the MMP9 promoter upon TGF-β stimulation and enhances TGF-β-mediated MMP9 upregulation and cell invasion.\",\n      \"method\": \"Co-immunoprecipitation, mammalian two-hybrid, GST pulldown, chromatin immunoprecipitation, luciferase reporter assay, invasion assay with siRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — three independent binding assays plus ChIP and functional knockdown\",\n      \"pmids\": [\"16619037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cited2 is a coactivator of HNF4α; physical interaction was demonstrated by co-IP. ChIP confirmed CITED2 is recruited to HNF4α-responsive promoters. Loss of Cited2 reduces HNF4α binding to target gene promoters in fetal liver, resulting in liver hypoplasia.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, Cited2 knockout mouse liver analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus ChIP plus genetic KO with defined molecular phenotype\",\n      \"pmids\": [\"17932483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CITED2 was identified as a direct PPARα-interacting protein; it binds predominantly via the ligand-binding domain of PPARα and acts as a dose-dependent coactivator of PPARα-dependent transcriptional regulation in reporter assays, independently of ligand.\",\n      \"method\": \"cDNA library interaction cloning with bacterially expressed PPARα, co-immunoprecipitation, transient transfection reporter assay, stable overexpression/siRNA knockdown cell lines, microarray\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction cloning plus reporter assay, single lab\",\n      \"pmids\": [\"15051727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CITED2 overexpression in Cited2−/− fibroblasts induces Bmi1 and Mel18 (polycomb-group genes) and decreases Ink4a/ARF expression, rescuing premature proliferation arrest. Deletion of Ink4a/ARF rescues defective proliferation of Cited2−/− fibroblasts. Bmi1 and Mel18 retroviruses rescue proliferation, placing them downstream of CITED2.\",\n      \"method\": \"Retroviral complementation, Ink4a/ARF genetic deletion in Cited2−/− background, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple compound mutants and retroviral rescue\",\n      \"pmids\": [\"14560011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CITED2 competes with MMP transactivator Ets-1 for binding to p300, thereby suppressing MMP-1 expression. Moderate flow shear (5 dyn/cm²) induces CITED2 via a TGF-β-dependent pathway, dissociates Ets-1 from p300, and associates CITED2 with p300. CITED2 induction requires p38δ phosphorylation.\",\n      \"method\": \"Competitive binding assay, transcription reporter assay, co-immunoprecipitation, antisense/sense CITED2 transfection, p38δ pharmacological inhibition\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — competitive binding assay plus co-IP plus functional reporter assay, in vitro and in vivo components\",\n      \"pmids\": [\"20826544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CITED2 is induced by fluid shear stress and suppresses MMP-1 and MMP-13 expression in chondrocytes. Overexpression represses MMP-1/MMP-13, antisense CITED2 prevents shear-induced downregulation. CITED2 associates with p300, displacing Ets-1 from p300, in a TGF-β-dependent manner.\",\n      \"method\": \"Sense/antisense CITED2 transfection, co-immunoprecipitation, MMP activity assay, flow shear cell culture system\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with molecular mechanism via co-IP\",\n      \"pmids\": [\"12960175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CITED2 constitutively localizes in the nucleus and interacts with p300, preventing p65 from binding to p300, impairing p65 acetylation, and reducing p65 binding to NF-κB-responsive promoters. LPS induces CITED2 expression via NF-κB, establishing a negative feedback loop. CITED2 sensitizes cells to TNF-α-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assay, siRNA knockdown, CITED2 overexpression, LPS stimulation of macrophages\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, ChIP, and gain/loss-of-function with defined molecular mechanism\",\n      \"pmids\": [\"21098220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CITED2 inactivates HIF-1α N-terminal transactivation domain (NAD) activity by interfering with NAD binding to the CH1 domain of p300, while also blocking C-terminal TAD-p300 interaction; NAD interacts with both CH1 and CH3 domains of p300, but CITED2 only blocks CH1 binding.\",\n      \"method\": \"Co-immunoprecipitation, reporter assay for NAD- and CAD-dependent genes, domain mapping\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and reporter assay, single lab\",\n      \"pmids\": [\"21925214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CITED2 is degraded via the ubiquitin-proteasome pathway; proteasome inhibition (MG132) stabilizes CITED2 protein, which then inactivates HIF-1 by blocking HIF-1α-p300 interaction, explaining the paradoxical reduction of HIF-1 activity despite HIF-1α protein accumulation upon proteasome inhibition.\",\n      \"method\": \"Proteasome inhibitor MG132 treatment, CITED2 siRNA knockdown, reporter assay, Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function rescue with defined molecular pathway, single lab\",\n      \"pmids\": [\"17906695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXL5 directly interacts with CITED2 and promotes its proteasome-dependent degradation; FBXL5 depletion increases CITED2 protein levels, whereas FBXL5 overexpression decreases them. FBXL5-mediated CITED2 degradation impairs CITED2-CH1(p300) interaction and enables HIF-1α N-terminal TAD transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference, overexpression, reporter assay, mouse embryonic stem cells\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and RNAi with functional reporter, single lab\",\n      \"pmids\": [\"25956243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 interacts with MYC and recruits p300 to promote MYC-p300-mediated transactivation of E2F3, driving G1/S cell cycle progression. CITED2 also interacts with HDAC1 and potentiates MYC-HDAC1 complex formation to suppress p21CIP1, inhibiting cellular quiescence.\",\n      \"method\": \"Co-immunoprecipitation, reporter assay, ChIP, siRNA knockdown, gain-of-function experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and ChIP plus functional phenotypic readouts, single lab\",\n      \"pmids\": [\"22814619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HIF-1α deletion partially rescues impaired HSC quiescence and reconstitution capacity caused by Cited2 deficiency, and restores p57 and Hes1 (but not Egr1) expression, indicating that CITED2 regulates HSC quiescence via both HIF-1-dependent and HIF-1-independent pathways.\",\n      \"method\": \"Conditional double-knockout mouse (Cited2/HIF-1α), flow cytometry, bone marrow transplantation, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with double-KO and defined molecular readouts\",\n      \"pmids\": [\"22308296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HIF-1α haploinsufficiency largely rescues outflow tract, interventricular septal, cardiac vascular, and hyposplenia defects in Cited2−/− embryos, and reduces HIF-1α-responsive gene mRNA levels in these hearts, providing in vivo evidence that CITED2 regulates cardiac development through inhibition of HIF-1 transcriptional activity.\",\n      \"method\": \"Cited2/HIF-1α compound mutant mouse, cardiac histology, MRI, gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue with HIF-1α haploinsufficiency, replicated in subsequent studies\",\n      \"pmids\": [\"17022961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 is recruited to the Oct4 promoter during early ESC differentiation to regulate Oct4 expression; loss of Cited2 delays silencing of pluripotency genes (Oct4, Klf4, Sox2, c-Myc) and impairs cardiomyocyte, hematopoietic, and neuronal differentiation.\",\n      \"method\": \"ChIP, gene knockout ESCs, qRT-PCR, differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus genetic KO with differentiation phenotype, single lab\",\n      \"pmids\": [\"22761414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cited2 directly targets Nanog, Tbx3, and Klf4 in ESCs; acute loss of Cited2 reduces Nanog expression and ESC self-renewal, and this is rescued by constitutive Nanog expression. Cited2 is also required for efficient reprogramming of fibroblasts to iPSCs.\",\n      \"method\": \"Inducible Cre-mediated acute deletion, ChIP, rescue by Nanog overexpression, reprogramming assay\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus genetic rescue with defined molecular targets, single lab\",\n      \"pmids\": [\"25377420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CITED2 interacts with WT1 and SF1 to promote Sry expression in the XY gonad above the threshold required for testis determination; reducing Wt1 or Sf1 dosage in Cited2 mutants produces XY sex reversal, defining Sry as a downstream target of the CITED2/WT1/SF1 regulatory pathway.\",\n      \"method\": \"Compound mutant mouse genetics, gene expression analysis, genetic epistasis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-allele genetic epistasis in vivo with quantitative expression correlates\",\n      \"pmids\": [\"19457926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 acts as a molecular chaperone guiding PRMT5 and p300 to nucleolin, thereby activating nucleolin and promoting epithelial-mesenchymal transition and prostate cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, xenograft mouse model, migration/invasion assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP with functional cellular phenotype, single lab\",\n      \"pmids\": [\"30291252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of Cited2 from heart progenitors (using cardiac-specific Cre) does not alter development; heart defects in Cited2-null embryos arise from an extra-cardiac requirement for Cited2 in establishing the left-right body axis. Cited2 also acts as a potentiator of BMP signaling to counteract Nodal initiation in the left lateral plate mesoderm.\",\n      \"method\": \"Conditional cardiac-specific knockout, molecular genetic analysis, gene expression studies\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional lineage-specific deletion dissecting cell-autonomous vs. non-autonomous requirement\",\n      \"pmids\": [\"21224256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Deletion of HIF-1α specifically in Cited2−/− lens eliminates excessive hyaloid vasculature hypercellularity without affecting the corneal-lenticular stalk phenotype; increased Pax6 dosage rescues the lens morphogenesis defect. This dissects two distinct CITED2 functions: one through HIF-1 in hyaloid vascular formation, and another upstream of or together with Pax6 in lens morphogenesis.\",\n      \"method\": \"Conditional double-knockout (lens-specific HIF-1α deletion in Cited2−/− background), Pax6 rescue genetics\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double conditional KO dissecting two independent pathways with specific molecular rescue\",\n      \"pmids\": [\"18653562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 is a direct effector of PPARγ; PPARγ binds the CITED2 promoter by ChIP, and PPARγ activation induces CITED2 expression in HCC cells. CITED2 knockdown increases cell viability and promotes G1-S transition; CITED2 overexpression suppresses HCC cell growth and upregulates CDK inhibitors p15, p21, p27.\",\n      \"method\": \"ChIP-PCR, adenovirus-PPARγ transduction, siRNA knockdown, gain-of-function proliferation assay\",\n      \"journal\": \"Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus gain/loss-of-function, single lab\",\n      \"pmids\": [\"23212831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CITED2 is recruited to the IKKα promoter (by ChIP) and directly regulates IKKα expression; CITED2 knockdown reduces IKKα, inhibits both canonical and noncanonical NF-κB signaling, and impairs breast cancer cell invasion. IKKα re-expression in CITED2-knockdown cells rescues invasive ability.\",\n      \"method\": \"ChIP, siRNA knockdown, IKKα rescue experiment, NF-κB reporter assay, invasion assay, xenograft\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus rescue experiment with defined molecular epistasis, single lab\",\n      \"pmids\": [\"27216153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CITED2 knockdown induces CBP/p300-mediated p53 acetylation at Lys373, reduces p53 ubiquitination, and stabilizes p53 protein, sensitizing cancer cells to cisplatin-induced apoptosis.\",\n      \"method\": \"shRNA knockdown, Western blot for p53 acetylation and ubiquitination, cisplatin sensitivity assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, loss-of-function with defined PTM readout but no direct interaction assay for CITED2-p300-p53\",\n      \"pmids\": [\"21660965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CITED2 signals through PPARγ to promote neuronal death after DNA damage; CITED2 upregulation is downstream of Cdk4 but upstream of the mitochondrial apoptotic pathway and independent of p53. CITED2 overexpression promotes cortical neuron death; CITED2 deficiency protects.\",\n      \"method\": \"Gene array, retroviral overexpression, CITED2 knockout neurons, Cdk4 inhibition, camptothecin DNA damage model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss-of-function with genetic epistasis placing CITED2 downstream of Cdk4 and upstream of mitochondrial apoptosis\",\n      \"pmids\": [\"18495890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cited2 is required for maintenance of glycolytic metabolism in adult HSCs; Cited2 deficiency reduces Pdk2, Pdk4, LDHB, and LDHD expression, increases mitochondrial activity and ROS, and elevated Akt/mTORC1 signaling. PI3K-Akt inhibition (but not mTORC1 inhibition alone) partially rescues Pdk4 repression.\",\n      \"method\": \"Conditional Cited2 knockout, metabolic assays (glycolysis, mitochondrial activity, ROS, ATP), gene expression, pharmacological rescue with PI3K and mTOR inhibitors\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with metabolic phenotyping and pharmacological rescue, single lab\",\n      \"pmids\": [\"24083546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TGF-β downregulates Cited2 post-transcriptionally via the Smad pathway (Smad4-dependent, Smad7-inhibitable) by accelerating Cited2 mRNA turnover; this requires the C-terminal conserved region of the Cited2 coding sequence. Cited2 transcription is not affected by TGF-β.\",\n      \"method\": \"Nuclear run-on assay, Cited2 promoter reporter assay, Smad4 knockdown/Smad7 overexpression, mRNA stability assay with transcriptional inhibitors, deletion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary approaches distinguishing transcriptional from post-transcriptional regulation, single lab\",\n      \"pmids\": [\"16675452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CITED2 is recruited to the Vegfa promoter in mouse embryonic hearts (by ChIP) and cooperates with TFAP2 to stimulate VEGFA promoter activity. Cardiomyocyte-specific Cited2 knockout results in compact layer thinning, reduced capillary density, and reduced Vegfa expression.\",\n      \"method\": \"Cardiomyocyte-specific conditional knockout, ChIP, transient transfection reporter assay, MRI, vessel morphometry\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with ChIP and reporter assay, multiple orthogonal methods\",\n      \"pmids\": [\"22504313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CITED2 is required for optimal PPARγ activation and anti-inflammatory gene expression in macrophages; CITED2 deficiency stabilizes HIF-1α protein, heightening proinflammatory gene expression. Overexpression of Egln3 or HIF-1α inhibition reverses elevated inflammation in Cited2-deficient macrophages. Myeloid-specific Cited2 KO mice are highly susceptible to endotoxin-induced sepsis.\",\n      \"method\": \"Myeloid-specific conditional knockout, gain- and loss-of-function, HIF-1α protein stability assay, Egln3 overexpression rescue, PPARγ reporter assay, LPS sepsis model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with genetic rescue and defined molecular epistasis, in vivo disease model\",\n      \"pmids\": [\"29203644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CITED2 deficiency in macrophages elevates IFNγ-induced STAT1 transcriptional activity, STAT1 enrichment on the IRF1 promoter, and IRF1-regulated pro-inflammatory gene expression. siRNA knockdown of IRF1 completely reverses elevated pro-inflammatory expression in CITED2-deficient macrophages. Myeloid CITED2-deficient mice on Apoe−/− background develop larger atherosclerotic lesions.\",\n      \"method\": \"Myeloid-specific conditional knockout, IRF1 siRNA rescue, ChIP for STAT1 at IRF1 promoter, atherosclerosis mouse model, transcriptomics/GSEA\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, genetic rescue, in vivo atherosclerosis model, multiple orthogonal methods\",\n      \"pmids\": [\"34365659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Indoxyl sulfate (uremic toxin) markedly upregulates CITED2 via post-transcriptional mRNA stabilization involving the ERK1/2 pathway. Elevated CITED2 impairs HIF-1α C-terminal transactivation domain (CTAD) function without altering HIF-1α protein levels, thereby suppressing hypoxia-inducible gene expression.\",\n      \"method\": \"Reporter assay for HIF-1α CTAD activity, qRT-PCR, ERK1/2 inhibition, mRNA stability experiments, in vivo CKD models\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — post-transcriptional mechanism with ERK inhibitor and reporter assay, in vivo validation, single lab\",\n      \"pmids\": [\"23792300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CITED2 is recruited to the Cebpa promoter in embryonic lung (by ChIP) in cooperation with Tcfap2c to activate Cebpa transcription, which is required for alveolar epithelial cell differentiation and lung maturation.\",\n      \"method\": \"ChIP in E18.5 lungs, Cited2 knockout lung phenotype, gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus genetic KO with defined molecular target, single lab\",\n      \"pmids\": [\"18358466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In sinusoidal trophoblast giant cells and syncytiotrophoblasts, CITED2 non-cell-autonomously patterns pericytes associated with embryonic capillaries, likely via PDGF signaling. Loss of CITED2 in syncytiotrophoblasts causes subcellular mislocalization of the lactate transporter SLC16A3 (MCT4).\",\n      \"method\": \"Conditional trophoblast-specific Cre deletion, histology, immunofluorescence for MCT4 localization, PDGF signaling analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with specific subcellular localization phenotype and proposed signaling mechanism, single lab\",\n      \"pmids\": [\"24803182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Computational structure-based modeling of TAZ1-CITED2-HIF-1α ternary system reveals that CITED2 forms the thermodynamically lowest energy complex with TAZ1 and binds TAZ1 faster kinetically than HIF-1α, explaining CITED2's superior competitive displacement of HIF-1α from p300.\",\n      \"method\": \"Structure-based computational modeling, free energy surface analysis, kinetic simulations\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational only, no in vitro experimental validation in this paper\",\n      \"pmids\": [\"32123067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A constrained (helix-stabilized) peptide derived from the CITED2 transactivation domain potently inhibits the HIF-1α–p300 interaction with high biochemical affinity, cell penetration, and serum stability, establishing that the CITED2-derived LPEL-containing helix is a pharmacologically tractable competitive inhibitor scaffold.\",\n      \"method\": \"In vitro binding affinity assay, cell penetration assay, serum stability assay, HIF-1α/p300 competition assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted competitive binding with constrained peptide, single study\",\n      \"pmids\": [\"34472840\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CITED2 is a nuclear transcriptional co-regulator that lacks intrinsic DNA-binding activity and functions primarily by binding with high affinity to the CH1 (TAZ1) domain of p300/CBP, thereby competing with HIF-1α (and other transcription factors) for co-activator recruitment; it co-activates TFAP2, HNF4α, PPARα/γ, SF-1 (via WT1), ISL1, Smad3, and estrogen receptor through p300/CBP bridging, while negatively regulating HIF-1α, NF-κB-p65, and STAT1-IRF1 by blocking their access to p300, and modulates gluconeogenesis by blocking GCN5-dependent PGC-1α acetylation in a glucagon-PKA-dependent manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CITED2 is an intrinsically disordered nuclear transcriptional co-regulator that modulates gene expression by bridging sequence-specific transcription factors to the acetyltransferase p300/CBP and by competitively displacing other p300/CBP-dependent activators from the CH1 (TAZ1) domain. Its transactivation domain folds upon binding to TAZ1 via a conserved LPEL motif, occupying a partially overlapping surface used by HIF-1α to effect potent competitive inhibition of HIF-1-dependent transcription — a mechanism validated structurally, genetically, and in vivo across cardiac development, hematopoietic stem cell maintenance, macrophage inflammation, and lens morphogenesis [PMID:12778114, PMID:12149478, PMID:19951693, PMID:29203644]. Simultaneously, CITED2 acts as a positive co-activator by recruiting p300/CBP to TFAP2, HNF4α, Smad2/3, WT1/SF-1, and MYC at target promoters including Pitx2c, Vegfa, Sry, and E2F3, and it modulates hepatic gluconeogenesis by blocking GCN5-mediated PGC-1α acetylation in a PKA-dependent signaling module [PMID:12586840, PMID:15475956, PMID:17932483, PMID:22426420, PMID:22814619]. CITED2 also suppresses NF-κB-p65 and STAT1-IRF1 signaling by sequestering p300, establishing anti-inflammatory negative feedback loops in macrophages relevant to endotoxemia and atherosclerosis [PMID:21098220, PMID:34365659].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The initial question was whether CITED2 had transcription factor partners beyond p300/CBP; the discovery that CITED2 physically interacts with and is required for TFAP2-dependent transactivation, combined with the severe Cited2-null phenotype, established it as a co-activator essential for cardiac, neural crest, and adrenal development.\",\n      \"evidence\": \"Co-IP, reporter assays, and Cited2 knockout mouse with lethal cardiac malformations and adrenal agenesis\",\n      \"pmids\": [\"11694877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CITED2–TFAP2 interface was not defined\", \"Whether cardiac defects were cell-autonomous was unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"This established the in vivo consequence of CITED2's competition with HIF-1α for p300/CBP: loss of Cited2 derepressed HIF-1 target genes in embryonic hearts and fibroblasts, confirming CITED2 as a physiological negative regulator of HIF-1 transcriptional activity.\",\n      \"evidence\": \"Cited2 knockout mouse with quantitative RT-PCR of HIF-1α target genes under hypoxia\",\n      \"pmids\": [\"12149478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of competitive displacement was structurally undefined at this point\", \"Whether HIF-1 derepression caused the cardiac defects was untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Two independent NMR structures resolved how CITED2's intrinsically disordered TAD folds upon binding to the TAZ1 (CH1) domain of p300/CBP and identified the conserved LPEL motif as the critical contact that overlaps with the HIF-1α binding surface, providing the atomic basis for competitive displacement.\",\n      \"evidence\": \"NMR solution structures of CITED2 TAD–p300 CH1 complex, mutagenesis of LPEL motif, in vivo co-IP\",\n      \"pmids\": [\"12778114\", \"14594809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetic parameters of displacement were not measured experimentally\", \"How CITED2 simultaneously co-activates TFAP2 while occupying the same CH1 domain was unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The ternary complex model was established: p300, TFAP2, and CITED2 form a physical complex in vivo, with CITED2 bridging TFAP2 to p300 in a HAT activity-dependent manner, resolving the question of how a co-activator lacking DNA-binding activity enhances transcription.\",\n      \"evidence\": \"Co-IP from U2-OS cells, mammalian two-hybrid, HAT-dead p300 mutant\",\n      \"pmids\": [\"12586840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this ternary model generalizes to other CITED2-dependent TF complexes was untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"CITED2 was placed upstream of polycomb-group gene regulation (Bmi1/Mel18) and Ink4a/ARF, explaining the premature senescence of Cited2-null fibroblasts and foreshadowing its role in stem cell maintenance.\",\n      \"evidence\": \"Retroviral complementation and Ink4a/ARF genetic deletion in Cited2−/− fibroblasts\",\n      \"pmids\": [\"14560011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional mechanism linking CITED2 to Bmi1/Mel18 was not defined\", \"Whether the same pathway operates in HSCs was unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"CITED2 and TFAP2 were shown to activate the Pitx2c promoter (by ChIP), placing CITED2 in the Nodal→Pitx2c left-right patterning pathway and explaining the laterality defects in Cited2-null embryos.\",\n      \"evidence\": \"ChIP in embryonic hearts, in situ hybridization in Cited2 knockout, reporter assay\",\n      \"pmids\": [\"15475956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CITED2 acts directly in the node or lateral plate mesoderm was unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Multiple new co-activation partnerships and a post-transcriptional regulatory mechanism were defined: CITED2 co-activates Smad2/3 at the MMP9 promoter upon TGF-β stimulation, and TGF-β also downregulates Cited2 mRNA post-transcriptionally via Smad4-dependent mRNA destabilization, revealing a complex TGF-β–CITED2 regulatory circuit.\",\n      \"evidence\": \"Co-IP, GST pulldown, mammalian two-hybrid for Smad interaction; nuclear run-on and mRNA stability assays for post-transcriptional regulation\",\n      \"pmids\": [\"16619037\", \"16675452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The RNA element mediating Cited2 mRNA destabilization was mapped only to the C-terminal coding region\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Genetic rescue of Cited2-null cardiac defects by HIF-1α haploinsufficiency provided definitive in vivo evidence that excess HIF-1 activity accounts for many of the cardiac malformations, validating the competitive displacement model at the organismal level.\",\n      \"evidence\": \"Cited2/HIF-1α compound mutant mouse with cardiac histology, MRI, and gene expression\",\n      \"pmids\": [\"17022961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Not all phenotypes were rescued, indicating HIF-1-independent CITED2 functions in cardiac development\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"CITED2 was established as a critical co-activator of WT1 and SF-1 to regulate adrenal and gonadal development, with compound mutant analysis showing dosage-sensitive control of Sf-1 expression — and separately, HNF4α coactivation was defined in fetal liver, broadening the portfolio of CITED2's tissue-specific TF partnerships.\",\n      \"evidence\": \"Cited2/Wt1/Sf-1 compound mutant genetics; co-IP and ChIP for HNF4α in fetal liver with Cited2 KO\",\n      \"pmids\": [\"17537799\", \"17932483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CITED2 directly bridges WT1 and p300 at Sf-1 promoters was not shown by ChIP\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"FOXO3a-mediated induction of CITED2 during hypoxia established a negative feedback loop limiting HIF-1 pro-apoptotic target gene expression, integrating CITED2 into the FOXO3a survival signaling network.\",\n      \"evidence\": \"Reporter assays and loss-of-function in fibroblasts and breast cancer cells\",\n      \"pmids\": [\"18158893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this loop operates in vivo in tumor hypoxia was not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Conditional deletion in adult mice revealed that CITED2 is essential cell-autonomously for HSC maintenance; concurrent Ink4a/Arf or Trp53 deletion rescued HSC function, connecting CITED2's earlier fibroblast senescence pathway to adult stem cell biology.\",\n      \"evidence\": \"Conditional Cre-mediated KO, bone marrow transplantation, genetic epistasis with Ink4a/Arf and Trp53\",\n      \"pmids\": [\"19951693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of CITED2 in HSCs were not comprehensively identified\", \"How CITED2 regulates p53 at the molecular level was unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"CITED2's mechanism as a competitive inhibitor was extended to NF-κB signaling: nuclear CITED2 sequesters p300 from p65, impairing p65 acetylation and DNA binding, while LPS induces CITED2 via NF-κB itself, forming a negative feedback loop in macrophages.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assay, siRNA knockdown and overexpression in LPS-stimulated macrophages\",\n      \"pmids\": [\"21098220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this mechanism accounts for CITED2's anti-inflammatory function in vivo was not tested at this point\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A metabolic regulatory function was uncovered: CITED2 blocks GCN5-mediated PGC-1α acetylation to enhance gluconeogenic gene expression during fasting, with CITED2 abundance itself regulated by glucagon-cAMP-PKA signaling and opposed by insulin-PI3K-Akt signaling.\",\n      \"evidence\": \"Co-IP, mouse genetic model, reporter assays, pharmacological PI3K-Akt inhibition\",\n      \"pmids\": [\"22426420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CITED2 directly interacts with GCN5 or acts through an intermediary was not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"In HSCs, HIF-1α deletion partially but not completely rescued Cited2-deficiency phenotypes, genetically dissecting HIF-1-dependent (quiescence genes p57, Hes1) from HIF-1-independent (Egr1) functions of CITED2 in stem cell maintenance.\",\n      \"evidence\": \"Conditional double-knockout (Cited2/HIF-1α), flow cytometry, bone marrow transplantation\",\n      \"pmids\": [\"22308296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the HIF-1-independent pathway mediating Egr1 regulation was unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"CITED2 was shown to interact with MYC and recruit p300 to transactivate E2F3 for G1/S progression, while also potentiating MYC-HDAC1-mediated repression of p21, revealing dual co-activator and co-repressor roles in cell cycle control.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown, reporter assay\",\n      \"pmids\": [\"22814619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CITED2-MYC interaction is direct or p300-mediated was not fully resolved\", \"In vivo relevance for tumorigenesis was not demonstrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The GCN5-CITED2-PKA module was further refined: PKA phosphorylates GCN5 in a CITED2-dependent manner, switching GCN5 substrate preference from PGC-1α to histones at gluconeogenic promoters, achieving simultaneous epigenetic activation and coactivator deacetylation.\",\n      \"evidence\": \"In vitro kinase assay, HAT activity assay, co-IP, mouse genetic models\",\n      \"pmids\": [\"27874008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The phosphorylation site on GCN5 was not mapped\", \"Whether this module operates in non-hepatic tissues was untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Tissue-specific conditional knockouts clarified that CITED2's role in cardiac outflow tract patterning is extra-cardiac (acting via left-right axis), while cardiomyocyte-specific deletion revealed a separate, cell-autonomous requirement for CITED2–TFAP2 co-activation of Vegfa in myocardial vascularization.\",\n      \"evidence\": \"Cardiac-specific vs. cardiomyocyte-specific conditional KO, ChIP at Vegfa promoter, MRI, vessel morphometry\",\n      \"pmids\": [\"21224256\", \"22504313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CITED2 regulates Vegfa independently of HIF-1α in cardiomyocytes was not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CITED2 deficiency in macrophages was shown to elevate STAT1-IRF1 pro-inflammatory signaling by increasing STAT1 enrichment at the IRF1 promoter, with myeloid CITED2 deletion exacerbating atherosclerosis, demonstrating a new anti-inflammatory axis beyond NF-κB and HIF-1.\",\n      \"evidence\": \"Myeloid conditional KO on Apoe−/− background, ChIP for STAT1 at IRF1, IRF1 siRNA rescue, transcriptomics\",\n      \"pmids\": [\"34365659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CITED2 directly competes with STAT1 for p300 or acts through another mechanism was not determined\", \"Relative contribution of HIF-1, NF-κB, and STAT1-IRF1 pathways to the atherosclerosis phenotype was not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the full structural basis of how CITED2 simultaneously co-activates diverse transcription factors while competitively inhibiting others at the same p300 CH1 domain, the identity and regulation of E3 ligases beyond FBXL5 controlling CITED2 turnover, and whether the GCN5-CITED2-PKA gluconeogenic module operates in metabolic tissues beyond liver.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full ternary structure of CITED2–p300–any partner TF exists\", \"CITED2 ubiquitination sites and comprehensive E3 ligase regulation remain incomplete\", \"Comprehensive ChIP-seq/CUT&RUN genome-wide occupancy studies in primary tissues are lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 4, 5, 8, 11, 12, 17, 21, 26, 36, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4, 7, 15, 17, 18, 37]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6, 8, 9, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 5, 11, 17, 24, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 11, 12, 17, 21, 36, 38]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 9, 15, 16, 31, 37]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 5, 6, 23, 26, 28, 29, 36, 40]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 37, 38]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 9, 34]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 7, 19, 39]}\n    ],\n    \"complexes\": [\n      \"p300/CBP-CITED2-TFAP2 ternary complex\",\n      \"GCN5-CITED2-PKA signaling module\"\n    ],\n    \"partners\": [\n      \"EP300\",\n      \"CREBBP\",\n      \"TFAP2A\",\n      \"HIF1A\",\n      \"WT1\",\n      \"SMAD3\",\n      \"HNF4A\",\n      \"KAT2A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}