{"gene":"CITED2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2003,"finding":"NMR structure of CITED2 transactivation domain bound to the CBP TAZ1 (CH1) domain reveals that CITED2 TAD is intrinsically disordered and folds upon binding, forming a helix (αA) and extended structure that wraps around TAZ1. CITED2 and HIF-1α share an overlapping 'LP(E/Q)L' binding hot spot on CH1 but use partly non-overlapping surfaces, allowing competitive displacement of HIF-1α by CITED2.","method":"NMR structure determination of CITED2 TAD-CBP TAZ1 complex; competitive binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution NMR structure with complementary binding competition data, consistent with independent structural study (PMID:12778114)","pmids":["14594809"],"is_preprint":false},{"year":2003,"finding":"High-resolution solution structure of the CITED2 TAD bound to the p300/CBP CH1 domain shows CITED2 TAD folds on the helical Zn2+-containing CH1 scaffold and disrupts the HIF-1α C-TAD–CH1 complex by binding CH1 with higher affinity via an overlapping 'LPXL' motif. Mutation of the LPEL sequence in full-length CITED2 abolishes p300 binding in vivo.","method":"High-resolution NMR solution structure; in vitro competition binding; LPEL mutagenesis with in vivo p300-binding assay","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure combined with mutagenesis and in vivo binding validation, replicated structurally by independent lab (PMID:14594809)","pmids":["12778114"],"is_preprint":false},{"year":2001,"finding":"CITED2 physically interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2A/B/C). Transactivation by TFAP2 isoforms is defective in Cited2−/− mouse embryonic fibroblasts and is rescued by ectopic CITED2. Loss of Cited2 causes cardiac malformations, adrenal agenesis, neural crest defects, and exencephaly in mice.","method":"Co-immunoprecipitation; rescue transactivation assay in knockout fibroblasts; Cited2 null mouse phenotyping","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus loss-of-function rescue in genetically defined cells, replicated in multiple subsequent studies","pmids":["11694877"],"is_preprint":false},{"year":2003,"finding":"p300/CBP, CITED2, and TFAP2A form a trimeric complex in vivo (co-IP from transfected cells). CITED2 interacts with the dimerization domain of TFAP2C (conserved in TFAP2A/B). Full-length p300 interacts with TFAP2A only when CITED2 is co-transfected (mammalian two-hybrid). A HAT-deficient p300 mutant (D1399Y) fails to co-activate TFAP2A and fails to interact with TFAP2A, indicating that HAT activity of p300 is required for TFAP2A co-activation.","method":"Co-immunoprecipitation from transfected U2-OS cells; mammalian two-hybrid; reporter co-activation assay with p300 HAT mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, two-hybrid, reporter assay with HAT mutant) in single study, consistent with PMID:11694877","pmids":["12586840"],"is_preprint":false},{"year":2002,"finding":"Cited2 functions as a negative regulator of HIF-1α transcriptional activity in vivo: Cited2−/− embryonic hearts show elevated mRNA levels of HIF-1α-responsive genes (VEGF, Glut1, PGK1), and Cited2−/− fibroblasts display enhanced expression of HIF-1α-responsive genes under hypoxia, consistent with competitive inhibition of HIF-1α binding to CBP/p300.","method":"Cited2 null mouse model; quantitative RT-PCR of HIF-1α target genes in knockout hearts and fibroblasts under hypoxia","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with defined molecular readout, replicated across independent Cited2-null lines","pmids":["12149478"],"is_preprint":false},{"year":2004,"finding":"CITED2 controls left-right patterning through a Nodal→Pitx2c pathway. CITED2 and TFAP2 proteins are detected at the Pitx2c promoter in embryonic hearts (ChIP), and they activate Pitx2c transcription in transient transfection assays. Cited2−/− mice lack Nodal, Pitx2c, and Ebaf expression in the left lateral plate mesoderm.","method":"Chromatin immunoprecipitation (ChIP) from embryonic hearts; transient transfection reporter assays; Cited2 null mouse gene expression analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus functional reporter plus in vivo loss-of-function with defined pathway placement, replicated in subsequent studies","pmids":["15475956"],"is_preprint":false},{"year":2007,"finding":"FOXO3a induces CITED2 transcription during hypoxia in an HIF-1-dependent manner. CITED2, in turn, functions in a negative feedback loop to reduce HIF-1 activity, resulting in reduced expression of proapoptotic HIF-1 target genes NIX and RTP801, thereby inhibiting HIF-1-induced apoptosis.","method":"Transcriptional reporter assays; siRNA knockdown of FOXO3a and CITED2; measurement of HIF-1 target gene expression in fibroblasts and breast cancer cells under hypoxia","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple loss-of-function experiments with defined pathway placement in single study, single lab","pmids":["18158893"],"is_preprint":false},{"year":2007,"finding":"Cited2 interacts with WT1 to stimulate expression of SF-1 (Nr5a1) in the adrenogonadal primordium (AGP) above the threshold required for adrenal cortex specification. Genetic reduction of Cited2 or Wt1 dosage proportionally reduces SF-1 levels in the AGP and impairs adrenal development; Sf-1/Cited2 double heterozygotes confirm they act in the same pathway.","method":"Mouse genetic epistasis (double heterozygotes, compound mutants); gene expression analysis (immunostaining, qPCR)","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple allelic combinations defining pathway position and dosage sensitivity","pmids":["17537799"],"is_preprint":false},{"year":2004,"finding":"CITED2 is a coactivator of PPARα: it interacts directly with PPARα predominantly via the ligand-binding domain (identified by interaction cloning), acts as a dose-dependent transcriptional coactivator of PPARα-dependent reporter genes in the presence of ligands, and also coactivates PPARγ but not PPARβ.","method":"cDNA library interaction cloning with bacterially expressed PPARα; GST pull-down; transient transfection reporter assays; stable overexpression/siRNA knockdown in hepatocytes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction cloning plus direct binding plus functional reporter assays, single lab","pmids":["15051727"],"is_preprint":false},{"year":2003,"finding":"CITED2 is upregulated by flow shear (5 dyn/cm²) in human chondrocytes and downregulates MMP-1 and MMP-13 mRNA and enzyme activity. CITED2 associates with p300, displacing Ets-1 from p300, thereby suppressing Ets-1-dependent MMP transcription. TGF-β stimulation promotes both CITED2 expression and its association with p300.","method":"Sense/antisense CITED2 overexpression under flow shear; co-immunoprecipitation of CITED2-p300 and p300-Ets-1 complexes; MMP activity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function plus Co-IP mechanism, single lab","pmids":["12960175"],"is_preprint":false},{"year":2006,"finding":"CITED2 physically interacts with Smad2 and Smad3 (co-IP, mammalian two-hybrid, GST pull-down). p300 enhances the CITED2–Smad3 interaction and transcriptional responses. CITED2 is recruited to the MMP9 promoter upon TGF-β stimulation (ChIP). CITED2 enhances TGF-β-mediated MMP9 upregulation and knockdown of CITED2 attenuates TGF-β-induced MMP9 expression and cell invasion.","method":"Co-immunoprecipitation; mammalian two-hybrid; GST pull-down; chromatin immunoprecipitation; siRNA knockdown; invasion assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, two-hybrid, GST pull-down, ChIP, functional invasion assay) in single study","pmids":["16619037"],"is_preprint":false},{"year":2012,"finding":"CITED2 is required for hepatic gluconeogenesis: it inhibits acetylation of PGC-1α by blocking its interaction with the acetyltransferase GCN5, reducing PGC-1α acetylation and increasing its coactivation of gluconeogenic genes. Glucagon-cAMP-PKA signaling increases hepatic CITED2 abundance; insulin–PI3K–Akt signaling disrupts the CITED2–GCN5 interaction. Loss of hepatic CITED2 suppresses gluconeogenesis in diabetic mice.","method":"Conditional knockout mice; co-immunoprecipitation (CITED2-GCN5 interaction); PGC-1α acetylation assay; gluconeogenic gene expression analysis; in vivo glucose production assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined molecular mechanism (Co-IP, acetylation assay) and in vivo metabolic phenotype","pmids":["22426420"],"is_preprint":false},{"year":2016,"finding":"During fasting, PKA phosphorylates GCN5 in a CITED2-dependent manner, increasing GCN5 histone acetyltransferase activity while attenuating its activity toward PGC-1α. This CITED2-dependent substrate switch of GCN5 simultaneously promotes epigenetic activation of gluconeogenic gene promoters and PGC-1α-mediated coactivation, thereby triggering gluconeogenesis.","method":"In vitro kinase assay (PKA phosphorylation of GCN5); histone acetyltransferase activity assay; ChIP; gluconeogenic gene expression in CITED2-deficient mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase and HAT assays plus ChIP plus in vivo knockout, single lab","pmids":["27874008"],"is_preprint":false},{"year":2007,"finding":"CITED2 is required for normal fetal liver hematopoiesis: Cited2−/− fetal liver shows reduced Lin−c-Kit+Sca-1+ cells and progenitors of all lineages, severely impaired colony formation, and compromised primary and secondary transplantation reconstitution of T, B, and myeloid lineages.","method":"Cited2 null mouse model; flow cytometry; colony-forming assay; competitive bone marrow transplantation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function null mouse with multiple orthogonal hematopoietic readouts including transplantation","pmids":["17644732"],"is_preprint":false},{"year":2009,"finding":"Cited2 is selectively and cell-autonomously required for adult hematopoietic stem cell (HSC) maintenance. Conditional deletion of Cited2 causes loss of HSCs and multilineage bone marrow failure. Additional deletion of Ink4a/Arf or Trp53 (p53) restores HSC functionality and rescues mice from bone marrow failure, placing Cited2 upstream of the Ink4a/Arf–p53 axis in HSC maintenance.","method":"Conditional knockout (Mx1-Cre); bone marrow transplantation; genetic epistasis with Ink4a/Arf and Trp53 null alleles; flow cytometry","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus genetic epistasis defining pathway, multiple orthogonal readouts, replicated across labs","pmids":["19951693"],"is_preprint":false},{"year":2012,"finding":"HIF-1α deletion partially rescues impaired HSC quiescence and reconstitution capacity caused by Cited2 deficiency, and restores expression of p57 and Hes1 but not Egr1, indicating that CITED2 regulates HSC quiescence through both HIF-1-dependent and HIF-1-independent pathways.","method":"Double-conditional knockout (Cited2 and HIF-1α); bone marrow transplantation; flow cytometry; transcriptional profiling","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with defined molecular targets, multiple orthogonal readouts","pmids":["22308296"],"is_preprint":false},{"year":2003,"finding":"Cited2 controls fibroblast proliferation via the polycomb-group genes Bmi1 and Mel18: Cited2−/− fibroblasts show premature proliferative arrest with increased p16INK4a, p19ARF, and p15INK4b expression and reduced Bmi1/Mel18 levels. Deletion of INK4a/ARF completely rescues proliferative defects of Cited2−/− fibroblasts. Bmi1 and Mel18 retroviruses also rescue proliferation, placing them downstream of Cited2.","method":"Cited2 null mouse embryonic fibroblasts; INK4a/ARF genetic rescue; retroviral complementation with CITED2, Bmi1, Mel18","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus retroviral complementation defining pathway order with specific proliferative phenotype","pmids":["14560011"],"is_preprint":false},{"year":2007,"finding":"Cited2 is a coactivator of HNF4α and is essential for fetal liver development. CITED2 physically interacts with HNF4α and is recruited to HNF4α-responsive promoters (ChIP). In the absence of Cited2, HNF4α binding to its target gene promoters is reduced.","method":"Cited2 null mouse fetal liver; co-immunoprecipitation (CITED2–HNF4α); chromatin immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus ChIP in null mouse model establishing direct physical and functional interaction","pmids":["17932483"],"is_preprint":false},{"year":2011,"finding":"CITED2 attenuates hypoxic activation of HIF-1α N-terminal transactivation domain (NAD)-dependent genes in addition to C-terminal TAD (CAD)-dependent genes. NAD interacts with both CH1 and CH3 domains of p300; CITED2 blocks NAD binding to CH1 but not CH3. pVHL also inhibits NAD activity by blocking the p300-NAD interaction.","method":"Co-immunoprecipitation (NAD-CH1, NAD-CH3 interactions); reporter gene assays for NAD- and CAD-dependent targets; siRNA knockdown","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP domain mapping plus reporter assays, single lab","pmids":["21925214"],"is_preprint":false},{"year":2010,"finding":"CITED2 constitutively localizes in the nucleus and interacts with p300, preventing p65 (NF-κB) from binding to p300, impairing p65 acetylation and p65 binding to target promoters. LPS induces CITED2 expression via NF-κB in macrophages, establishing a negative feedback loop. CITED2 also sensitizes cells to TNF-α-induced apoptosis.","method":"Subcellular fractionation/nuclear localization imaging; co-immunoprecipitation (CITED2-p300, p65-p300); p65 acetylation assay; ChIP; ectopic expression and knockdown reporter assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IP and functional assays in single lab establishing negative feedback mechanism","pmids":["21098220"],"is_preprint":false},{"year":2007,"finding":"CITED2 is degraded via the ubiquitin-proteasome system and is stabilized by proteasome inhibitors. Stabilized CITED2 inhibits HIF-1α C-terminal transactivation domain (CAD) activity and blocks p300 recruitment by HIF-1α, explaining the paradoxical reduction of HIF-1α transcriptional activity upon proteasome inhibition.","method":"Proteasome inhibitor treatment (MG132); CITED2 siRNA rescue; co-immunoprecipitation (HIF-1α-p300); reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic rescue with siRNA plus Co-IP, single lab","pmids":["17906695"],"is_preprint":false},{"year":2006,"finding":"TGF-β downregulates CITED2 mRNA post-transcriptionally via the Smad pathway (requires Smad4, blocked by Smad7 overexpression), accelerating turnover of Cited2 transcripts. The C-terminal conserved coding region of Cited2 is required for TGF-β-mediated mRNA destabilization. Transcriptional rate is not affected.","method":"Nuclear run-on analysis; promoter reporter assay; Smad7 overexpression/Smad4 knockdown; transcript turnover assay with transcription inhibitors; heterologous promoter-driven Cited2 coding sequence constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic approaches distinguishing transcriptional vs post-transcriptional regulation, single lab","pmids":["16675452"],"is_preprint":false},{"year":2009,"finding":"CITED2 acts within the WT1/SF1 regulatory pathway in the gonad to increase Sry expression above the threshold required for testis determination. Reducing Wt1 or Sf1 gene dosage in Cited2 mutants produces partial XY sex reversal, and a hypomorphic SryPOS allele causes full sex reversal, placing Sry as a downstream target of the CITED2/WT1/SF1 pathway.","method":"Genetic epistasis in mice (Cited2, Wt1, Sf1 compound mutants; SryPOS allele); gene expression analysis of Sry and Sf1 during sex determination","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multi-allele genetic epistasis in vivo with quantitative expression analysis defining pathway order","pmids":["19457926"],"is_preprint":false},{"year":2010,"finding":"Loss of Cited2 from heart progenitors (Nkx2-5-Cre) does not alter cardiac development, whereas extra-cardiac deletion establishes that heart defects in Cited2-null embryos arise from failure to establish the left-right body axis. Cited2 is identified as a potentiator of BMP signalling that counteracts initiation of Nodal expression in the left lateral plate mesoderm.","method":"Conditional knockout (multiple Cre drivers); epistasis with BMP signaling pathway; gene expression analysis in node and LPM","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional lineage-specific knockout with multiple Cre lines defining extra-cardiac requirement and pathway position","pmids":["21224256"],"is_preprint":false},{"year":2012,"finding":"CITED2 functions as a molecular switch between TGF-α-induced proliferation and TGF-β-mediated quiescence: upon TGF-α induction, CITED2 is induced by MYC and recruits p300 to promote MYC-p300-mediated transactivation of E2F3, driving G1/S progression. CITED2 also interacts with HDAC1 and potentiates MYC-HDAC1-mediated suppression of p21CIP1. TGF-β downregulates CITED2, abolishing these effects.","method":"Co-immunoprecipitation (CITED2-p300, CITED2-HDAC1, MYC-HDAC1 complexes); reporter assays; siRNA knockdown; overexpression; cell cycle analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IP interactions plus functional reporter and phenotypic assays, single lab","pmids":["22814619"],"is_preprint":false},{"year":2008,"finding":"CITED2 acts as a coactivator of liver-enriched transcription factor HNF4α for fetal liver development; in neurons, CITED2 is upregulated by DNA damage downstream of Cdk4 and activates PPARγ, which is required for DNA damage-induced neuronal apoptosis. CITED2 overexpression promotes death and CITED2 deficiency protects; Cdk4 blockade prevents CITED2 induction.","method":"Gene array plus RT-PCR/Western blot in camptothecin-treated neurons; CITED2 overexpression/knockdown with apoptosis assay; Cdk4 inhibitor; PPARγ reporter assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple gain/loss-of-function experiments defining pathway order (Cdk4→CITED2→PPARγ→apoptosis), single lab","pmids":["18495890"],"is_preprint":false},{"year":2012,"finding":"CITED2 is recruited to the Oct4 promoter during early embryonic stem cell differentiation (ChIP) and regulates Oct4 expression. Loss of Cited2 delays silencing of pluripotency genes (Oct4, Klf4, Sox2, c-Myc) and impairs cardiomyocyte, hematopoietic, and neuronal differentiation.","method":"Cited2 knockout ESCs; chromatin immunoprecipitation (CITED2 at Oct4 promoter); differentiation assays; gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct promoter occupancy plus loss-of-function phenotype, single lab","pmids":["22761414"],"is_preprint":false},{"year":2012,"finding":"CITED2 is a direct effector of PPARγ in hepatocellular carcinoma: PPARγ activation induces CITED2 expression and is the most prominent PPARγ-bound target gene by ChIP-PCR. CITED2 knockdown increases cell viability and promotes G1-S transition, while ectopic CITED2 suppresses HCC cell growth associated with upregulation of CDK inhibitors and tumor suppressor genes.","method":"Chromatin immunoprecipitation (PPARγ at CITED2 promoter); loss- and gain-of-function assays; cell cycle analysis","journal":"Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional gain/loss-of-function with cell cycle readout, single lab","pmids":["23212831"],"is_preprint":false},{"year":2015,"finding":"FBXL5 directly interacts with CITED2 and targets it for proteasomal degradation. Depletion of FBXL5 by RNAi increases CITED2 protein levels; overexpression of FBXL5 decreases CITED2 levels in a proteasome-dependent manner, impairs CITED2–CH1(p300) interaction, and enables HIF-1α N-terminal transactivation domain activity.","method":"Co-immunoprecipitation (CITED2-FBXL5); RNAi knockdown of FBXL5; proteasome inhibitor rescue; CITED2-CH1 interaction assay in living cells; HIF-1α TAD reporter assay","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional proteasome-dependent degradation assay plus reporter, single lab","pmids":["25956243"],"is_preprint":false},{"year":2010,"finding":"Moderate mechanical loading (2.5 MPa, 1 Hz intermittent hydrostatic pressure) upregulates CITED2 in chondrocytes via p38δ phosphorylation. CITED2 suppresses MMP-1 expression by competing with Ets-1 for binding to p300 (demonstrated by competitive binding and transcription assays). In vivo, daily passive joint motion prevents MMP-1 upregulation and cartilage degradation coincident with CITED2 induction.","method":"Competitive binding assay (CITED2 vs Ets-1 for p300); transcription assays; in vitro hydrostatic pressure system; in vivo hind-limb immobilization model; p38δ-specific inhibition/phosphorylation analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive binding assay plus in vitro and in vivo mechanistic experiments, single lab","pmids":["20826544"],"is_preprint":false},{"year":2008,"finding":"In nucleus pulposus cells, HIF-2α preferentially regulates CITED2 expression and promoter activity under hypoxia (unlike HIF-1α's predominant role in most other tissues). Forced expression or suppression of CITED2 causes corresponding changes in VEGF expression, establishing CITED2 as a regulator of VEGF in this cell type.","method":"HIF-2α/HIF-1α siRNA suppression; gain- and loss-of-function CITED2 constructs; promoter activity assays; VEGF expression measurement","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple constructs establishing mechanistic link, single lab","pmids":["19035510"],"is_preprint":false},{"year":2011,"finding":"CITED2 knockdown induces CBP/p300-mediated p53 acetylation at Lys373, decreases p53 ubiquitination, and stabilizes p53 protein, sensitizing cancer cells to cisplatin-induced apoptosis in a p53-dependent manner.","method":"shRNA knockdown; p53 acetylation assay (Lys373); p53 ubiquitination assay; cisplatin cytotoxicity in p53-positive vs p53-defective cell lines","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical acetylation/ubiquitination assays plus p53-status-dependent functional comparison, single lab","pmids":["21660965"],"is_preprint":false},{"year":2015,"finding":"CITED2 silencing reduces ERCC1 expression and impairs p53-dependent chromatin relaxation (H3K9Ac, H3K14Ac) at the ERCC1 promoter in response to cisplatin. ChIP shows p53 and acetylated histones bind the ERCC1 promoter upon cisplatin treatment in a CITED2/p300-dependent manner, establishing a CITED2/p300/p53/ERCC1 pathway in DNA damage response.","method":"shRNA knockdown; chromatin immunoprecipitation (p53, H3K9Ac, H3K14Ac at ERCC1 promoter); ERCC1 reporter; DNA damage comet assay; xenograft model","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with multiple histone marks plus functional DNA repair assay, single lab","pmids":["26384430"],"is_preprint":false},{"year":2012,"finding":"CITED2 cardiomyocyte-specific knockout (Cited2Nkx) causes ventricular septal defects and compact layer thinning associated with reduced capillary density and 1.5-fold reduction in Vegfa expression. ChIP confirms CITED2 occupancy at the Vegfa promoter in mouse embryonic hearts; CITED2 activates human VEGFA promoter cooperatively with TFAP2 in transient transfection assays.","method":"Cardiomyocyte-specific conditional knockout; histology and MRI; chromatin immunoprecipitation (CITED2 at Vegfa promoter); transient transfection reporter assay","journal":"European heart journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP and functional reporter assay establishing direct regulation of Vegfa","pmids":["22504313"],"is_preprint":false},{"year":2008,"finding":"Cited2 and Tcfap2c complex is present at the Cebpa promoter in E18.5 lungs (ChIP) and activates Cebpa transcription. Loss of Cited2 reduces Cebpa expression in fetal lungs and impairs alveolar epithelial cell differentiation.","method":"Cited2 null mouse lung; chromatin immunoprecipitation (Cited2, Tcfap2c at Cebpa promoter); gene expression analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function null mouse with specific molecular target, single lab","pmids":["18358466"],"is_preprint":false},{"year":2018,"finding":"CITED2 acts as a molecular chaperone guiding PRMT5 and p300 to nucleolin, thereby activating nucleolin. The CITED2-nucleolin axis stimulates cell migration through epithelial-mesenchymal transition and promotes prostate cancer metastasis in a xenograft model.","method":"Co-immunoprecipitation (CITED2-PRMT5, CITED2-p300, CITED2-nucleolin); functional migration/invasion assays; xenograft mouse model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing ternary complex plus functional in vivo xenograft, single lab","pmids":["30291252"],"is_preprint":false},{"year":2018,"finding":"CITED2 deficiency in macrophages elevates HIF-1α protein stability and proinflammatory cytokine/chemokine gene expression; overexpression of Egln3 (a prolyl hydroxylase) or HIF-1α inhibition completely reverses elevated proinflammatory gene expression in Cited2-deficient macrophages. CITED2 also promotes PPARγ activation and anti-inflammatory gene expression.","method":"Myeloid-specific conditional knockout; Egln3 overexpression rescue; HIF-1α inhibition rescue; gain- and loss-of-function reporter assays; endotoxin sepsis model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus genetic/pharmacologic rescue defining pathway, in vivo sepsis model","pmids":["29203644"],"is_preprint":false},{"year":2021,"finding":"CITED2 deficiency in macrophages elevates STAT1 transcriptional activity and IRF1 expression; siRNA-mediated knockdown of IRF1 completely reverses elevated proinflammatory gene expression in CITED2-deficient macrophages. Myeloid-CITED2-deficient mice on Apoe−/− background develop larger atherosclerotic lesions.","method":"Myeloid-specific conditional knockout; ChIP (STAT1 enrichment on IRF1 promoter); IRF1 siRNA rescue; atherosclerosis lesion quantification","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus ChIP plus epistatic siRNA rescue defining STAT1-IRF1 pathway, in vivo atherosclerosis model","pmids":["34365659"],"is_preprint":false},{"year":2016,"finding":"CITED2 is recruited to the IKKα promoter in breast cancer cells (ChIP), directly regulating IKKα expression. CITED2 knockdown reduces IKKα and several NF-κB target genes; restoration of IKKα rescues the invasive ability lost upon CITED2 knockdown, demonstrating a CITED2→IKKα→NF-κB axis in breast cancer metastasis.","method":"Chromatin immunoprecipitation (CITED2 at IKKα promoter); shRNA knockdown; IKKα rescue experiment; invasion assay; xenograft model","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus epistatic rescue experiment with functional invasion readout, single lab","pmids":["27216153"],"is_preprint":false},{"year":2016,"finding":"CITED2 is recruited to the CCL20 promoter in MDA-MB-231 breast cancer cells (ChIP), and CITED2 knockdown reduces CCL20 expression and attenuates macrophage recruitment both in vitro and in orthotopic tumors.","method":"Chromatin immunoprecipitation (CITED2 at CCL20 promoter); shRNA knockdown; Transwell macrophage recruitment assay; orthotopic xenograft","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional macrophage recruitment assay in vitro and in vivo, single lab","pmids":["29399152"],"is_preprint":false},{"year":2016,"finding":"CITED2 cooperates physically with ISL1 (co-immunoprecipitation) and together they promote cardiomyocyte differentiation from mouse ESCs. Loss of Cited2 impairs early mesoderm and cardiogenic transcription factor expression (Isl1, Gata4, Tbx5); CITED2 recombinant protein rescues cardiogenic defects in Cited2-depleted cells.","method":"Co-immunoprecipitation (CITED2-ISL1); Cited2 knockdown in ESC differentiation; recombinant protein rescue; cardiac differentiation assay","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus loss-of-function and protein rescue, single lab","pmids":["27818139"],"is_preprint":false},{"year":2015,"finding":"Cited2 directly targets Nanog, Tbx3, and Klf4 in mouse ESCs and is required for their expression; constitutive Nanog expression partially rescues the proliferation, survival, and self-renewal defects caused by Cited2 depletion, positioning Nanog downstream of Cited2 in the pluripotency network.","method":"Acute Cited2 deletion in ESCs; ChIP (CITED2 at Nanog/Tbx3/Klf4 loci); Nanog overexpression rescue; self-renewal assay","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus epistatic rescue placing Nanog downstream of CITED2, single lab","pmids":["25377420"],"is_preprint":false},{"year":2013,"finding":"Cited2 is recruited to the hexokinase 1 (HK1) gene promoter (ChIP) in mouse ESCs to regulate HK1 transcription, coordinating glucose metabolism. Cited2 knockout ESCs show enhanced glycolysis, reduced glucose oxidation, abnormal mitochondrial morphology, and decreased ATP, correlated with defective differentiation under hypoxia.","method":"Cited2 knockout ESCs; chromatin immunoprecipitation (CITED2 at HK1 promoter); metabolic assays (glycolysis, oxygen consumption, ATP); differentiation assay under hypoxia","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus comprehensive metabolic phenotyping in KO cells, single lab","pmids":["24265312"],"is_preprint":false},{"year":2013,"finding":"Cited2 deficiency in adult HSCs reduces expression of Pdk2, Pdk4, LDHB, and LDHD, leading to decreased glycolysis, elevated reactive oxygen species, and increased mitochondrial activity. Inhibition of PI3K/Akt (but not mTORC1) partially restores Pdk4 expression in Cited2-deficient HSCs.","method":"Conditional knockout HSCs; metabolic assays (glycolysis, mitochondrial activity, ROS); PI3K/Akt and mTORC1 inhibitors; gene expression analysis","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with pharmacologic pathway dissection and metabolic readouts, single lab","pmids":["24083546"],"is_preprint":false},{"year":2013,"finding":"Indoxyl sulfate upregulates CITED2 through post-transcriptional mRNA stabilization involving the ERK1/2 pathway (not HIF-1α protein level changes), thereby functionally impairing HIF-1α C-terminal transactivation domain activity and suppressing HIF-1 target genes.","method":"mRNA stability assay; ERK1/2 pathway inhibition; HIF-1α CTAD reporter; protein and mRNA quantification in HK-2 cells","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay plus pathway inhibition identifying ERK1/2-dependent mechanism, single lab","pmids":["23792300"],"is_preprint":false},{"year":2012,"finding":"CITED2 is phosphorylated by MAPK1 (ERK2) in vitro at T166 within the SRJ domain. MAPK1 activation enhances the TFAP2 coactivation function of CITED2 but not of the T166N mutant, establishing T166 as a regulatory phosphorylation site for CITED2 coactivation activity.","method":"In vitro kinase assay (MAPK1 phosphorylation of CITED2); T166N point mutation; TFAP2 coactivation reporter assay; knock-in mouse (no morphological phenotype with T166N or ΔSRJ alleles)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional reporter, single lab; in vivo knock-in did not produce phenotype","pmids":["23082118"],"is_preprint":false},{"year":2021,"finding":"CITED2 is required for expression of key HSC regulators GATA2, MCL-1, and PTEN. Hematopoietic-specific MCL-1 overexpression partially rescues the Cited2-deficient HSC pool and reconstitution potential. Cited2;Pten compound heterozygotes show decreased HSC numbers and failed reconstitution, placing PTEN downstream of CITED2.","method":"Hematopoietic-specific conditional knockout; MCL-1 transgenic rescue; Cited2;Pten compound heterozygotes; bone marrow transplantation; transcriptomics/GSEA","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus genetic rescue (MCL-1 transgene) plus compound heterozygote epistasis defining GATA2/MCL-1/PTEN as direct targets","pmids":["34715054"],"is_preprint":false},{"year":2023,"finding":"CITED2 is distinctively expressed in junctional zone and invasive trophoblast cells in rat placenta and in extravillous trophoblast (EVT) cell columns in human placenta. Homozygous Cited2 deletion disrupts the junctional zone, delays intrauterine trophoblast invasion, and compromises trophoblast plasticity, establishing CITED2 as a conserved regulator of deep hemochorial placentation.","method":"Cited2 null rat and human trophoblast loss-of-function; immunofluorescence localization; trophoblast invasion assays; EVT lineage differentiation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — cross-species loss-of-function (rat null + human trophoblast) with direct localization and functional invasion readout","pmids":["36626551"],"is_preprint":false}],"current_model":"CITED2 is a nuclear, intrinsically disordered transcriptional co-regulator that binds with high affinity to the CH1/TAZ1 domain of CBP/p300 through an LPXL motif, competitively displacing HIF-1α and thereby acting as a negative feedback regulator of hypoxic gene expression; it simultaneously co-activates transcription factors including TFAP2A/B/C, HNF4α, PPARα/γ, Smad2/3, estrogen receptor, and ISL1 by bridging them to p300/CBP, and it modulates the GCN5 acetyltransferase substrate switch to control PGC-1α-dependent gluconeogenesis, regulates NF-κB and STAT1-IRF1 inflammatory signalling in macrophages, controls fibroblast and HSC proliferation via Bmi1/Mel18-INK4a/ARF-p53, drives left-right patterning through a Nodal→Pitx2c pathway in concert with TFAP2, and is subject to regulation by post-translational modifications including MAPK1-mediated phosphorylation at T166 and FBXL5-directed proteasomal degradation."},"narrative":{"mechanistic_narrative":"CITED2 is a nuclear, intrinsically disordered transcriptional co-regulator that operates principally by competing for the CH1/TAZ1 domain of the coactivators CBP/p300, thereby reprogramming which transcription factors gain access to p300's acetyltransferase activity [PMID:14594809, PMID:12778114]. Its transactivation domain folds upon binding the zinc-containing CH1 scaffold through an 'LPXL' hot spot that overlaps the HIF-1α binding surface, allowing CITED2 to displace HIF-1α from p300 and act as a negative-feedback brake on hypoxic gene expression — a loop induced by FOXO3a and HIF-1 itself, and that limits both C-terminal and N-terminal HIF-1α transactivation domain activity [PMID:14594809, PMID:12778114, PMID:12149478, PMID:18158893, PMID:21925214]. Conversely, CITED2 bridges p300/CBP to a broad set of sequence-specific factors to activate transcription, most prominently the TFAP2 family, with which it forms a trimeric p300–CITED2–TFAP2 complex requiring p300 HAT activity [PMID:11694877, PMID:12586840]; it likewise co-activates HNF4α, PPARα/γ, Smad2/3, and ISL1 and occupies target promoters including Pitx2c, Vegfa, Cebpa, Oct4, and Nanog [PMID:15475956, PMID:15051727, PMID:16619037, PMID:17932483, PMID:22504313, PMID:18358466, PMID:27818139, PMID:25377420]. Through these activities CITED2 controls left-right body-axis establishment via a BMP-counteracting Nodal→Pitx2c pathway [PMID:15475956, PMID:21224256], adrenal and gonadal specification via the WT1/SF1 axis [PMID:17537799, PMID:19457926], fetal and adult hematopoietic stem cell maintenance upstream of the Ink4a/ARF–p53 axis and GATA2/MCL-1/PTEN [PMID:17644732, PMID:19951693, PMID:14560011, PMID:34715054], hepatic gluconeogenesis by modulating the GCN5 acetyltransferase substrate switch on PGC-1α [PMID:22426420, PMID:27874008], and inflammatory signalling in macrophages by restraining HIF-1α- and STAT1-IRF1-driven proinflammatory programs [PMID:29203644, PMID:34365659]. CITED2 abundance and activity are tuned by post-translational control, including FBXL5-directed proteasomal degradation and MAPK1 phosphorylation at T166 in the SRJ domain that enhances TFAP2 coactivation [PMID:25956243, PMID:23082118]. Loss-of-function mouse and rat models tie these molecular roles to cardiac, neural crest, hematopoietic, and placental developmental defects [PMID:11694877, PMID:22504313, PMID:36626551].","teleology":[{"year":2001,"claim":"Established the first defined molecular partner and developmental role for CITED2 by showing it co-activates the TFAP2 transcription factor family, framing it as a transcriptional coactivator rather than an orphan protein.","evidence":"Co-IP, transactivation rescue in Cited2-null fibroblasts, and Cited2 null mouse phenotyping","pmids":["11694877"],"confidence":"High","gaps":["Did not resolve how CITED2 bridges TFAP2 to the general transcription machinery","Mechanism connecting molecular defect to the diverse null phenotypes unaddressed"]},{"year":2002,"claim":"Defined CITED2's signature activity as a negative regulator of HIF-1α, explaining how it dampens hypoxic gene expression in vivo.","evidence":"Cited2 null mice with qRT-PCR of HIF-1α target genes in hearts and fibroblasts under hypoxia","pmids":["12149478"],"confidence":"High","gaps":["Structural basis of HIF-1α displacement not yet shown","Whether inhibition extends beyond C-terminal HIF-1α transactivation unknown"]},{"year":2003,"claim":"Solved the structural mechanism of competition, showing the disordered CITED2 TAD folds on the p300/CBP CH1 domain and outcompetes HIF-1α at an overlapping LPXL hot spot.","evidence":"NMR solution structures of the CITED2 TAD–CH1/TAZ1 complex, competitive binding assays, and LPEL mutagenesis with in vivo p300 binding","pmids":["12778114","14594809"],"confidence":"High","gaps":["Did not address how CITED2 selectively recruits versus displaces partners at the same surface","Affinity differences across the many CITED2-CBP-dependent factors not quantified"]},{"year":2003,"claim":"Showed CITED2 nucleates a trimeric p300–CITED2–TFAP2 complex whose coactivation depends on p300 HAT activity, and extended the displacement principle to Ets-1, linking CITED2 to MMP suppression under mechanical/TGF-β cues.","evidence":"Co-IP, mammalian two-hybrid, reporter assays with a HAT-deficient p300 mutant, and competitive p300-binding assays in chondrocytes","pmids":["12586840","12960175"],"confidence":"High","gaps":["Acetylation substrates relevant to TFAP2 targets not identified","Generality of Ets-1 displacement across cell types untested"]},{"year":2003,"claim":"Placed CITED2 upstream of a polycomb–INK4a/ARF axis controlling proliferation, establishing a developmentally relevant growth-control pathway.","evidence":"Cited2-null MEFs with INK4a/ARF genetic rescue and retroviral Bmi1/Mel18 complementation","pmids":["14560011"],"confidence":"High","gaps":["Direct transcriptional targets linking CITED2 to Bmi1/Mel18 not defined","Whether effect is p300-dependent unaddressed"]},{"year":2004,"claim":"Connected CITED2 to body-axis patterning through a Nodal→Pitx2c pathway acting with TFAP2 at the Pitx2c promoter.","evidence":"ChIP from embryonic hearts, transient reporter assays, and Cited2-null gene expression analysis","pmids":["15475956"],"confidence":"High","gaps":["How CITED2 initiates left-sided Nodal expression not resolved","Cardiac versus extra-cardiac origin of defects unclear at this stage"]},{"year":2004,"claim":"Broadened the coactivator repertoire to nuclear receptors by demonstrating direct, ligand-dependent coactivation of PPARα and PPARγ.","evidence":"Interaction cloning, GST pull-down, reporter assays, and overexpression/knockdown in hepatocytes","pmids":["15051727"],"confidence":"Medium","gaps":["Single-lab finding without structural confirmation","PPAR target genes in vivo not defined here"]},{"year":2006,"claim":"Identified CITED2 as a Smad2/3 partner and showed it is itself post-transcriptionally downregulated by TGF-β, defining a regulated CITED2-TGF-β node controlling MMP9 and invasion.","evidence":"Co-IP, two-hybrid, GST pull-down, ChIP at MMP9, knockdown invasion assays, and transcript turnover analysis","pmids":["16619037","16675452"],"confidence":"Medium","gaps":["RNA-binding factor mediating TGF-β-driven mRNA destabilization unidentified","Reconciliation of CITED2 promoting MMP9 here yet suppressing MMP-1/13 elsewhere unaddressed"]},{"year":2007,"claim":"Established CITED2 within feedback and developmental gene circuits: a FOXO3a/HIF-1-induced antiapoptotic feedback loop, a coactivator of HNF4α for fetal liver, a WT1/SF1-pathway component for adrenal specification, and a requirement for fetal liver hematopoiesis.","evidence":"Reporter and knockdown assays under hypoxia; Co-IP and ChIP in null livers; mouse genetic epistasis; transplantation assays","pmids":["18158893","17932483","17537799","17644732"],"confidence":"High","gaps":["Whether these roles share the common p300-bridging mechanism not directly tested across contexts","Direct CITED2 targets in hematopoietic progenitors not yet defined"]},{"year":2009,"claim":"Defined a cell-autonomous requirement for CITED2 in adult HSC maintenance acting upstream of the Ink4a/ARF–p53 axis, and extended the WT1/SF1 pathway to Sry-dependent testis determination.","evidence":"Conditional knockout with Ink4a/Arf and Trp53 epistasis and transplantation; multi-allele genetic epistasis with Wt1/Sf1/Sry","pmids":["19951693","19457926"],"confidence":"High","gaps":["Direct transcriptional link between CITED2 and Ink4a/Arf repression not shown","Molecular mechanism setting Sry expression threshold unresolved"]},{"year":2010,"claim":"Generalized the p300-displacement mechanism to NF-κB p65 and resolved that CITED2 cardiac defects arise extra-cardiacally from failed left-right axis establishment, with CITED2 acting as a BMP potentiator.","evidence":"Co-IP and p65 acetylation/ChIP assays in macrophages; lineage-specific conditional knockouts with BMP epistasis","pmids":["21098220","21224256"],"confidence":"Medium","gaps":["In vivo NF-κB targets restrained by CITED2 not yet mapped","Mechanistic link between BMP potentiation and Nodal suppression incomplete"]},{"year":2011,"claim":"Expanded HIF inhibition to the N-terminal transactivation domain and revealed that CITED2 levels also tune p53 acetylation/stability and drug sensitivity through p300.","evidence":"Co-IP domain mapping and reporter assays; shRNA knockdown with p53 acetylation/ubiquitination and cisplatin cytotoxicity assays","pmids":["21925214","21660965"],"confidence":"Medium","gaps":["Both single-lab; how CITED2 selectively gates p53 versus HIF access to p300 unclear","In vivo relevance of CITED2-p53 axis not established"]},{"year":2012,"claim":"Defined a major metabolic role: CITED2 controls hepatic gluconeogenesis by blocking GCN5-mediated PGC-1α acetylation, integrating glucagon/insulin signalling, and directly regulates Vegfa with TFAP2 in the developing heart.","evidence":"Conditional knockout mice, Co-IP, PGC-1α acetylation and glucose-production assays; cardiomyocyte-specific knockout with ChIP and reporter at Vegfa","pmids":["22426420","22504313"],"confidence":"High","gaps":["How signalling-driven changes in CITED2 abundance are achieved mechanistically not fully resolved","Coordination of metabolic versus coactivator roles within the same cell unaddressed"]},{"year":2012,"claim":"Implicated CITED2 in pluripotency and cell-cycle control, occupying the Oct4 promoter during ESC differentiation and acting as a MYC/p300 versus HDAC1 switch between proliferation and quiescence; also identified it as a PPARγ effector tumor suppressor and a Cdk4→CITED2→PPARγ neuronal apoptosis mediator.","evidence":"ChIP and knockout ESC differentiation; Co-IP of CITED2-p300/HDAC1/MYC with cell-cycle assays; PPARγ ChIP and gain/loss-of-function; neuronal apoptosis assays","pmids":["22761414","22814619","23212831","18495890"],"confidence":"Medium","gaps":["Context determining pro- versus anti-proliferative outcome not defined","All single-lab with limited cross-validation"]},{"year":2013,"claim":"Linked CITED2 to cellular metabolism by direct promoter regulation of glycolytic genes (HK1) in ESCs and metabolic gene programs (Pdk2/4, LDH) in HSCs, coupling its transcriptional role to glucose handling and ROS control.","evidence":"ChIP and metabolic phenotyping in knockout ESCs and conditional-knockout HSCs with PI3K/Akt inhibition; ERK1/2-dependent mRNA stabilization in renal cells","pmids":["24265312","24083546","23792300"],"confidence":"Medium","gaps":["Whether metabolic gene regulation is direct p300-bridged coactivation untested","Single-lab metabolic readouts"]},{"year":2015,"claim":"Defined an FBXL5-directed proteasomal degradation route controlling CITED2 abundance and HIF-1α access to p300, and placed CITED2/p300 upstream of p53-dependent ERCC1 chromatin remodeling in DNA damage response.","evidence":"Co-IP, RNAi, proteasome-dependent degradation and CITED2-CH1 interaction assays; ChIP of p53 and histone acetylation at ERCC1 with DNA-repair assays","pmids":["25956243","26384430"],"confidence":"Medium","gaps":["Degron and ubiquitination sites on CITED2 not mapped","Both single-lab without reciprocal validation"]},{"year":2016,"claim":"Refined regulatory inputs and outputs: established MAPK1 phosphorylation at T166 as a tunable enhancer of TFAP2 coactivation, demonstrated a GCN5 substrate-switch mechanism for gluconeogenesis, and identified CITED2-driven IKKα/NF-κB and CCL20 programs in breast cancer alongside cooperation with ISL1 in cardiogenesis.","evidence":"In vitro kinase assays with T166N mutant; PKA/GCN5 kinase and HAT assays with ChIP; ChIP and rescue/invasion/macrophage-recruitment assays; Co-IP with ISL1 and ESC cardiac differentiation","pmids":["23082118","27874008","27216153","29399152","27818139"],"confidence":"Medium","gaps":["T166N knock-in produced no morphological phenotype, leaving physiological importance of this site uncertain","Cancer-promoting versus tumor-suppressing roles of CITED2 not reconciled mechanistically"]},{"year":2018,"claim":"Demonstrated CITED2 restrains macrophage inflammation by limiting HIF-1α stability and promoting PPARγ activity, and identified a chaperone-like role guiding PRMT5/p300 to activate nucleolin in cancer metastasis.","evidence":"Myeloid-specific knockout with Egln3/HIF-1α rescue and sepsis model; Co-IP of CITED2-PRMT5/p300/nucleolin with migration and xenograft assays","pmids":["29203644","30291252"],"confidence":"Medium","gaps":["Whether nucleolin chaperone role uses the same CH1-binding surface unknown","Direct CITED2 control of HIF-1α prolyl-hydroxylase pathway not fully defined"]},{"year":2021,"claim":"Identified additional macrophage and HSC effectors of CITED2, defining a STAT1-IRF1 inflammatory axis and GATA2/MCL-1/PTEN as required HSC targets with in vivo disease relevance.","evidence":"Myeloid conditional knockout with ChIP and IRF1 siRNA rescue plus atherosclerosis model; hematopoietic conditional knockout with MCL-1 transgenic rescue and Pten compound heterozygote epistasis","pmids":["34365659","34715054"],"confidence":"High","gaps":["Whether GATA2/MCL-1/PTEN are direct CITED2/p300 transcriptional targets not fully shown","Integration of metabolic and survival programs in HSCs unresolved"]},{"year":2023,"claim":"Extended CITED2's developmental requirement to placentation, identifying it as a conserved regulator of trophoblast invasion and junctional-zone integrity.","evidence":"Cited2 null rat and human trophoblast loss-of-function with localization and invasion/EVT differentiation assays","pmids":["36626551"],"confidence":"High","gaps":["Transcriptional targets driving trophoblast invasion not defined","Whether the role depends on HIF competition or TFAP2 coactivation unaddressed"]},{"year":null,"claim":"How CITED2 selects between displacing (HIF-1α, p65, Ets-1) and recruiting (TFAP2, HNF4α, nuclear receptors, ISL1) factors at the same p300/CBP CH1 surface, and what determines its context-specific pro- versus anti-proliferative and pro- versus anti-tumor outcomes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling competitive inhibition and coactivation at CH1","Cell-type determinants of opposing growth outcomes undefined","Quantitative affinity hierarchy among CITED2-CBP-dependent partners not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,5,8,17,33]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,18,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[35]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,6,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,5,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,7,22,23,33,47]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,36,37]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,12,42,43]}],"complexes":["p300/CBP–CITED2–TFAP2 trimeric complex"],"partners":["EP300","CREBBP","TFAP2A","HIF1A","HNF4A","SMAD3","ISL1","FBXL5"],"other_free_text":[]}},"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 co-activator.","date":"2001","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11694877","citation_count":282,"is_preprint":false},{"pmid":"18158893","id":"PMC_18158893","title":"FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18158893","citation_count":237,"is_preprint":false},{"pmid":"12149478","id":"PMC_12149478","title":"The essential role of Cited2, a negative regulator for HIF-1alpha, in heart development and neurulation.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12149478","citation_count":179,"is_preprint":false},{"pmid":"12778114","id":"PMC_12778114","title":"Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2.","date":"2003","source":"Nature structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/12778114","citation_count":176,"is_preprint":false},{"pmid":"15475956","id":"PMC_15475956","title":"Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15475956","citation_count":175,"is_preprint":false},{"pmid":"12586840","id":"PMC_12586840","title":"Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12586840","citation_count":132,"is_preprint":false},{"pmid":"11823447","id":"PMC_11823447","title":"Folic acid prevents exencephaly in Cited2 deficient mice.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11823447","citation_count":132,"is_preprint":false},{"pmid":"15750185","id":"PMC_15750185","title":"Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development.","date":"2005","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15750185","citation_count":114,"is_preprint":false},{"pmid":"12960175","id":"PMC_12960175","title":"CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12960175","citation_count":111,"is_preprint":false},{"pmid":"16287139","id":"PMC_16287139","title":"Identification and functional analysis of CITED2 mutations in patients with congenital heart defects.","date":"2005","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16287139","citation_count":104,"is_preprint":false},{"pmid":"17537799","id":"PMC_17537799","title":"Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17537799","citation_count":104,"is_preprint":false},{"pmid":"15051727","id":"PMC_15051727","title":"Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15051727","citation_count":101,"is_preprint":false},{"pmid":"14594809","id":"PMC_14594809","title":"Interaction of the TAZ1 domain of the CREB-binding protein with the activation domain of CITED2: regulation by competition between intrinsically unstructured ligands for non-identical binding sites.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14594809","citation_count":97,"is_preprint":false},{"pmid":"16579983","id":"PMC_16579983","title":"Loss of Cited2 affects trophoblast formation and vascularization of the mouse placenta.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16579983","citation_count":94,"is_preprint":false},{"pmid":"16619037","id":"PMC_16619037","title":"Cited2 modulates TGF-beta-mediated upregulation of MMP9.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16619037","citation_count":93,"is_preprint":false},{"pmid":"19951693","id":"PMC_19951693","title":"Cited2 is an essential regulator of adult hematopoietic stem cells.","date":"2009","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/19951693","citation_count":91,"is_preprint":false},{"pmid":"17615577","id":"PMC_17615577","title":"Cited1 and Cited2 are differentially expressed in the developing kidney but are not required for nephrogenesis.","date":"2007","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/17615577","citation_count":78,"is_preprint":false},{"pmid":"14560011","id":"PMC_14560011","title":"Transcriptional coactivator Cited2 induces Bmi1 and Mel18 and controls fibroblast proliferation via Ink4a/ARF.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14560011","citation_count":77,"is_preprint":false},{"pmid":"20826544","id":"PMC_20826544","title":"Physiological loading of joints prevents cartilage degradation through CITED2.","date":"2010","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/20826544","citation_count":74,"is_preprint":false},{"pmid":"22426420","id":"PMC_22426420","title":"CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis.","date":"2012","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22426420","citation_count":66,"is_preprint":false},{"pmid":"17932483","id":"PMC_17932483","title":"Cited2, a coactivator of HNF4alpha, is essential for liver development.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17932483","citation_count":66,"is_preprint":false},{"pmid":"22814619","id":"PMC_22814619","title":"CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence.","date":"2012","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/22814619","citation_count":65,"is_preprint":false},{"pmid":"19035510","id":"PMC_19035510","title":"Cited2 modulates hypoxia-inducible factor-dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc.","date":"2008","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/19035510","citation_count":64,"is_preprint":false},{"pmid":"30291252","id":"PMC_30291252","title":"Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30291252","citation_count":63,"is_preprint":false},{"pmid":"21098220","id":"PMC_21098220","title":"Negative feedback regulation of NF-κB action by CITED2 in the nucleus.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21098220","citation_count":62,"is_preprint":false},{"pmid":"26240138","id":"PMC_26240138","title":"MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26240138","citation_count":55,"is_preprint":false},{"pmid":"21224256","id":"PMC_21224256","title":"Loss of Cited2 causes congenital heart disease by perturbing left-right patterning of the body axis.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21224256","citation_count":53,"is_preprint":false},{"pmid":"22308296","id":"PMC_22308296","title":"HIF-1α deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22308296","citation_count":53,"is_preprint":false},{"pmid":"17022961","id":"PMC_17022961","title":"Partial rescue of defects in Cited2-deficient embryos by HIF-1alpha heterozygosity.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17022961","citation_count":50,"is_preprint":false},{"pmid":"18054336","id":"PMC_18054336","title":"A role for CITED2, a CBP/p300 interacting protein, in colon cancer cell invasion.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/18054336","citation_count":49,"is_preprint":false},{"pmid":"17644732","id":"PMC_17644732","title":"Cited2 is required for normal hematopoiesis in the murine fetal liver.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17644732","citation_count":49,"is_preprint":false},{"pmid":"18358466","id":"PMC_18358466","title":"Cited2 is required for fetal lung maturation.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18358466","citation_count":48,"is_preprint":false},{"pmid":"10552932","id":"PMC_10552932","title":"Molecular cloning and chromosomal localization of the human CITED2 gene encoding p35srj/Mrg1.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10552932","citation_count":47,"is_preprint":false},{"pmid":"18653562","id":"PMC_18653562","title":"Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18653562","citation_count":47,"is_preprint":false},{"pmid":"19457926","id":"PMC_19457926","title":"The transcription co-factor CITED2 functions during sex determination and early gonad development.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19457926","citation_count":46,"is_preprint":false},{"pmid":"22465428","id":"PMC_22465428","title":"Pan-histone deacetylase inhibitor panobinostat sensitizes gastric cancer cells to anthracyclines via induction of CITED2.","date":"2012","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/22465428","citation_count":45,"is_preprint":false},{"pmid":"24803182","id":"PMC_24803182","title":"Cited2 is required in trophoblasts for correct placental capillary patterning.","date":"2014","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/24803182","citation_count":44,"is_preprint":false},{"pmid":"23792300","id":"PMC_23792300","title":"Indoxyl sulfate signals for rapid mRNA stabilization of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) and suppresses the expression of hypoxia-inducible genes in experimental CKD and uremia.","date":"2013","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/23792300","citation_count":42,"is_preprint":false},{"pmid":"29203644","id":"PMC_29203644","title":"CITED2 Restrains Proinflammatory Macrophage Activation and Response.","date":"2018","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29203644","citation_count":39,"is_preprint":false},{"pmid":"24456003","id":"PMC_24456003","title":"CITED2 mutation and methylation in children with congenital heart disease.","date":"2014","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/24456003","citation_count":39,"is_preprint":false},{"pmid":"26450995","id":"PMC_26450995","title":"High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress.","date":"2015","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/26450995","citation_count":39,"is_preprint":false},{"pmid":"21660965","id":"PMC_21660965","title":"Knockdown of CITED2 using short-hairpin RNA sensitizes cancer cells to cisplatin through stabilization of p53 and enhancement of p53-dependent apoptosis.","date":"2011","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21660965","citation_count":38,"is_preprint":false},{"pmid":"19757380","id":"PMC_19757380","title":"Gonadal defects in Cited2-mutant mice indicate a role for SF1 in both testis and ovary differentiation.","date":"2010","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19757380","citation_count":37,"is_preprint":false},{"pmid":"32294623","id":"PMC_32294623","title":"Diabetes-induced glucolipotoxicity impairs wound healing ability of adipose-derived stem cells-through the miR-1248/CITED2/HIF-1α pathway.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32294623","citation_count":36,"is_preprint":false},{"pmid":"27874008","id":"PMC_27874008","title":"The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27874008","citation_count":36,"is_preprint":false},{"pmid":"19904269","id":"PMC_19904269","title":"CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer.","date":"2009","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19904269","citation_count":35,"is_preprint":false},{"pmid":"16675452","id":"PMC_16675452","title":"Post-transcriptional control of Cited2 by transforming growth factor beta. Regulation via Smads and Cited2 coding region.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16675452","citation_count":35,"is_preprint":false},{"pmid":"32849774","id":"PMC_32849774","title":"Long Non-coding RNA FGD5-AS1 Regulates Cancer Cell Proliferation and Chemoresistance in Gastric Cancer Through miR-153-3p/CITED2 Axis.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32849774","citation_count":34,"is_preprint":false},{"pmid":"20566713","id":"PMC_20566713","title":"Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left-right patterning defects.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20566713","citation_count":34,"is_preprint":false},{"pmid":"18440989","id":"PMC_18440989","title":"Epiblastic Cited2 deficiency results in cardiac phenotypic heterogeneity and provides a mechanism for haploinsufficiency.","date":"2008","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/18440989","citation_count":33,"is_preprint":false},{"pmid":"23212831","id":"PMC_23212831","title":"CITED2 is a novel direct effector of peroxisome proliferator-activated receptor γ in suppressing hepatocellular carcinoma cell growth.","date":"2012","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23212831","citation_count":33,"is_preprint":false},{"pmid":"21925214","id":"PMC_21925214","title":"CITED2 controls the hypoxic signaling by snatching p300 from the two distinct activation domains of HIF-1α.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21925214","citation_count":33,"is_preprint":false},{"pmid":"17906695","id":"PMC_17906695","title":"CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17906695","citation_count":32,"is_preprint":false},{"pmid":"29794136","id":"PMC_29794136","title":"The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29794136","citation_count":32,"is_preprint":false},{"pmid":"17499866","id":"PMC_17499866","title":"Regulation of Cited2 expression provides a functional link between translational and transcriptional responses during hypoxia.","date":"2007","source":"Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17499866","citation_count":31,"is_preprint":false},{"pmid":"30177819","id":"PMC_30177819","title":"GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2.","date":"2018","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30177819","citation_count":30,"is_preprint":false},{"pmid":"27307230","id":"PMC_27307230","title":"Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27307230","citation_count":29,"is_preprint":false},{"pmid":"25184385","id":"PMC_25184385","title":"CITED2-mediated human hematopoietic stem cell maintenance is critical for acute myeloid leukemia.","date":"2014","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/25184385","citation_count":28,"is_preprint":false},{"pmid":"34365659","id":"PMC_34365659","title":"CITED2 inhibits STAT1-IRF1 signaling and atherogenesis.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34365659","citation_count":27,"is_preprint":false},{"pmid":"34277611","id":"PMC_34277611","title":"CircSNHG5 Sponges Mir-495-3p and Modulates CITED2 to Protect Cartilage Endplate From Degradation.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34277611","citation_count":27,"is_preprint":false},{"pmid":"19642106","id":"PMC_19642106","title":"Identification of prospective factors promoting osteotropism in breast cancer: a potential role for CITED2.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19642106","citation_count":27,"is_preprint":false},{"pmid":"36626551","id":"PMC_36626551","title":"CITED2 is a conserved regulator of the uterine-placental interface.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36626551","citation_count":26,"is_preprint":false},{"pmid":"25956243","id":"PMC_25956243","title":"FBXL5 modulates HIF-1α transcriptional activity by degradation of CITED2.","date":"2015","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/25956243","citation_count":26,"is_preprint":false},{"pmid":"32697413","id":"PMC_32697413","title":"CITED2 limits pathogenic inflammatory gene programs in myeloid cells.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32697413","citation_count":25,"is_preprint":false},{"pmid":"22761414","id":"PMC_22761414","title":"Cited2 gene controls pluripotency and cardiomyocyte differentiation of murine embryonic stem cells through Oct4 gene.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22761414","citation_count":25,"is_preprint":false},{"pmid":"32728529","id":"PMC_32728529","title":"CITED2 and the modulation of the hypoxic response in cancer.","date":"2020","source":"World journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32728529","citation_count":24,"is_preprint":false},{"pmid":"22504313","id":"PMC_22504313","title":"A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development.","date":"2012","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/22504313","citation_count":24,"is_preprint":false},{"pmid":"18495890","id":"PMC_18495890","title":"CITED2 signals through peroxisome proliferator-activated receptor-gamma to regulate death of cortical neurons after DNA damage.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18495890","citation_count":24,"is_preprint":false},{"pmid":"17283246","id":"PMC_17283246","title":"CITED2 is expressed in human adrenocortical cells and regulated by basic fibroblast growth factor.","date":"2007","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17283246","citation_count":24,"is_preprint":false},{"pmid":"27216153","id":"PMC_27216153","title":"CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα.","date":"2016","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/27216153","citation_count":23,"is_preprint":false},{"pmid":"28084522","id":"PMC_28084522","title":"Downregulation of CITED2 contributes to TGFβ-mediated senescence of tendon-derived stem cells.","date":"2017","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/28084522","citation_count":23,"is_preprint":false},{"pmid":"30891766","id":"PMC_30891766","title":"CITED2 mediates the cross-talk between mechanical loading and IL-4 to promote chondroprotection.","date":"2019","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30891766","citation_count":23,"is_preprint":false},{"pmid":"23811274","id":"PMC_23811274","title":"CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23811274","citation_count":23,"is_preprint":false},{"pmid":"27818139","id":"PMC_27818139","title":"CITED2 Cooperates with ISL1 and Promotes Cardiac Differentiation of Mouse Embryonic Stem Cells.","date":"2016","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27818139","citation_count":22,"is_preprint":false},{"pmid":"25377420","id":"PMC_25377420","title":"Acute loss of Cited2 impairs Nanog expression and decreases self-renewal of mouse embryonic stem cells.","date":"2015","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/25377420","citation_count":22,"is_preprint":false},{"pmid":"22735262","id":"PMC_22735262","title":"CITED2 mutation links congenital heart defects to dysregulation of the cardiac gene VEGF and PITX2C expression.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22735262","citation_count":22,"is_preprint":false},{"pmid":"23082118","id":"PMC_23082118","title":"Functional significance of SRJ domain mutations in CITED2.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23082118","citation_count":21,"is_preprint":false},{"pmid":"27561725","id":"PMC_27561725","title":"Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells.","date":"2016","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/27561725","citation_count":21,"is_preprint":false},{"pmid":"17133411","id":"PMC_17133411","title":"Generation of conditional Cited2 null alleles.","date":"2006","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/17133411","citation_count":21,"is_preprint":false},{"pmid":"19032942","id":"PMC_19032942","title":"Overexpression of the transcriptional coregulator Cited2 protects against glucocorticoid-induced atrophy of C2C12 myotubes.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19032942","citation_count":21,"is_preprint":false},{"pmid":"29072699","id":"PMC_29072699","title":"CITED2 affects leukemic cell survival by interfering with p53 activation.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29072699","citation_count":20,"is_preprint":false},{"pmid":"24265312","id":"PMC_24265312","title":"Cited2, a transcriptional modulator protein, regulates metabolism in murine embryonic stem cells.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24265312","citation_count":20,"is_preprint":false},{"pmid":"27680315","id":"PMC_27680315","title":"Cited2 participates in cardiomyocyte apoptosis and maternal diabetes-induced congenital heart abnormality.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27680315","citation_count":20,"is_preprint":false},{"pmid":"32123067","id":"PMC_32123067","title":"Investigations of the underlying mechanisms of HIF-1α and CITED2 binding to TAZ1.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32123067","citation_count":20,"is_preprint":false},{"pmid":"11044621","id":"PMC_11044621","title":"Expression analysis of the chicken homologue of CITED2 during early stages of embryonic development.","date":"2000","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/11044621","citation_count":20,"is_preprint":false},{"pmid":"19632219","id":"PMC_19632219","title":"Conditional deletion of Cited2 results in defective corneal epithelial morphogenesis and maintenance.","date":"2009","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19632219","citation_count":19,"is_preprint":false},{"pmid":"26384430","id":"PMC_26384430","title":"CITED2 silencing sensitizes cancer cells to cisplatin by inhibiting p53 trans-activation and chromatin relaxation on the ERCC1 DNA repair gene.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26384430","citation_count":19,"is_preprint":false},{"pmid":"34472840","id":"PMC_34472840","title":"Potent Inhibition of HIF1α and p300 Interaction by a Constrained Peptide Derived from CITED2.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34472840","citation_count":19,"is_preprint":false},{"pmid":"33439552","id":"PMC_33439552","title":"Genetic analysis of the CITED2 gene promoter in isolated and sporadic congenital ventricular septal defects.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33439552","citation_count":18,"is_preprint":false},{"pmid":"24083546","id":"PMC_24083546","title":"Cited2 is required for the maintenance of glycolytic metabolism in adult hematopoietic stem cells.","date":"2013","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/24083546","citation_count":18,"is_preprint":false},{"pmid":"34715054","id":"PMC_34715054","title":"CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation.","date":"2021","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34715054","citation_count":17,"is_preprint":false},{"pmid":"32831926","id":"PMC_32831926","title":"Role of CITED2 in stem cells and cancer.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32831926","citation_count":16,"is_preprint":false},{"pmid":"29399152","id":"PMC_29399152","title":"CITED2 attenuates macrophage recruitment concordant with the downregulation of CCL20 in breast cancer cells.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29399152","citation_count":16,"is_preprint":false},{"pmid":"23507959","id":"PMC_23507959","title":"Cited2 in hematopoietic stem cell function.","date":"2013","source":"Current opinion in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/23507959","citation_count":15,"is_preprint":false},{"pmid":"33706167","id":"PMC_33706167","title":"A gain-of-function mutation in CITED2 is associated with congenital heart disease.","date":"2021","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/33706167","citation_count":15,"is_preprint":false},{"pmid":"19607804","id":"PMC_19607804","title":"Identification of CITED2 as a negative regulator of fracture healing.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19607804","citation_count":15,"is_preprint":false},{"pmid":"20392269","id":"PMC_20392269","title":"CITED2 mechanoregulation of matrix metalloproteinases.","date":"2010","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/20392269","citation_count":15,"is_preprint":false},{"pmid":"31515672","id":"PMC_31515672","title":"Novel Point Mutations of CITED2 Gene Are Associated with Non-familial Congenital Heart Disease (CHD) in Sporadic Pediatric Patients.","date":"2019","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31515672","citation_count":15,"is_preprint":false},{"pmid":"32242581","id":"PMC_32242581","title":"Competitive binding of HIF-1α and CITED2 to the TAZ1 domain of CBP from molecular simulations.","date":"2020","source":"Physical chemistry chemical physics : PCCP","url":"https://pubmed.ncbi.nlm.nih.gov/32242581","citation_count":15,"is_preprint":false},{"pmid":"26812245","id":"PMC_26812245","title":"Cited2 protein level in cumulus cells is a biomarker for human embryo quality and pregnancy outcome in one in vitro fertilization cycle.","date":"2016","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/26812245","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50804,"output_tokens":12315,"usd":0.168569,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24161,"output_tokens":7293,"usd":0.151565,"stage2_stop_reason":"end_turn"},"total_usd":0.320134,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"NMR structure of CITED2 transactivation domain bound to the CBP TAZ1 (CH1) domain reveals that CITED2 TAD is intrinsically disordered and folds upon binding, forming a helix (αA) and extended structure that wraps around TAZ1. CITED2 and HIF-1α share an overlapping 'LP(E/Q)L' binding hot spot on CH1 but use partly non-overlapping surfaces, allowing competitive displacement of HIF-1α by CITED2.\",\n      \"method\": \"NMR structure determination of CITED2 TAD-CBP TAZ1 complex; competitive binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution NMR structure with complementary binding competition data, consistent with independent structural study (PMID:12778114)\",\n      \"pmids\": [\"14594809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"High-resolution solution structure of the CITED2 TAD bound to the p300/CBP CH1 domain shows CITED2 TAD folds on the helical Zn2+-containing CH1 scaffold and disrupts the HIF-1α C-TAD–CH1 complex by binding CH1 with higher affinity via an overlapping 'LPXL' motif. Mutation of the LPEL sequence in full-length CITED2 abolishes p300 binding in vivo.\",\n      \"method\": \"High-resolution NMR solution structure; in vitro competition binding; LPEL mutagenesis with in vivo p300-binding assay\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure combined with mutagenesis and in vivo binding validation, replicated structurally by independent lab (PMID:14594809)\",\n      \"pmids\": [\"12778114\"],\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 (TFAP2A/B/C). Transactivation by TFAP2 isoforms is defective in Cited2−/− mouse embryonic fibroblasts and is rescued by ectopic CITED2. Loss of Cited2 causes cardiac malformations, adrenal agenesis, neural crest defects, and exencephaly in mice.\",\n      \"method\": \"Co-immunoprecipitation; rescue transactivation assay in knockout fibroblasts; Cited2 null mouse phenotyping\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus loss-of-function rescue in genetically defined cells, replicated in multiple subsequent studies\",\n      \"pmids\": [\"11694877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p300/CBP, CITED2, and TFAP2A form a trimeric complex in vivo (co-IP from transfected cells). CITED2 interacts with the dimerization domain of TFAP2C (conserved in TFAP2A/B). Full-length p300 interacts with TFAP2A only when CITED2 is co-transfected (mammalian two-hybrid). A HAT-deficient p300 mutant (D1399Y) fails to co-activate TFAP2A and fails to interact with TFAP2A, indicating that HAT activity of p300 is required for TFAP2A co-activation.\",\n      \"method\": \"Co-immunoprecipitation from transfected U2-OS cells; mammalian two-hybrid; reporter co-activation assay with p300 HAT mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, two-hybrid, reporter assay with HAT mutant) in single study, consistent with PMID:11694877\",\n      \"pmids\": [\"12586840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cited2 functions as a negative regulator of HIF-1α transcriptional activity in vivo: Cited2−/− embryonic hearts show elevated mRNA levels of HIF-1α-responsive genes (VEGF, Glut1, PGK1), and Cited2−/− fibroblasts display enhanced expression of HIF-1α-responsive genes under hypoxia, consistent with competitive inhibition of HIF-1α binding to CBP/p300.\",\n      \"method\": \"Cited2 null mouse model; quantitative RT-PCR of HIF-1α target genes in knockout hearts and fibroblasts under hypoxia\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with defined molecular readout, replicated across independent Cited2-null lines\",\n      \"pmids\": [\"12149478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CITED2 controls left-right patterning through a Nodal→Pitx2c pathway. CITED2 and TFAP2 proteins are detected at the Pitx2c promoter in embryonic hearts (ChIP), and they activate Pitx2c transcription in transient transfection assays. Cited2−/− mice lack Nodal, Pitx2c, and Ebaf expression in the left lateral plate mesoderm.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) from embryonic hearts; transient transfection reporter assays; Cited2 null mouse gene expression analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus functional reporter plus in vivo loss-of-function with defined pathway placement, replicated in subsequent studies\",\n      \"pmids\": [\"15475956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FOXO3a induces CITED2 transcription during hypoxia in an HIF-1-dependent manner. CITED2, in turn, functions in a negative feedback loop to reduce HIF-1 activity, resulting in reduced expression of proapoptotic HIF-1 target genes NIX and RTP801, thereby inhibiting HIF-1-induced apoptosis.\",\n      \"method\": \"Transcriptional reporter assays; siRNA knockdown of FOXO3a and CITED2; measurement of HIF-1 target gene expression in fibroblasts and breast cancer cells under hypoxia\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple loss-of-function experiments with defined pathway placement in single study, single lab\",\n      \"pmids\": [\"18158893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cited2 interacts with WT1 to stimulate expression of SF-1 (Nr5a1) in the adrenogonadal primordium (AGP) above the threshold required for adrenal cortex specification. Genetic reduction of Cited2 or Wt1 dosage proportionally reduces SF-1 levels in the AGP and impairs adrenal development; Sf-1/Cited2 double heterozygotes confirm they act in the same pathway.\",\n      \"method\": \"Mouse genetic epistasis (double heterozygotes, compound mutants); gene expression analysis (immunostaining, qPCR)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple allelic combinations defining pathway position and dosage sensitivity\",\n      \"pmids\": [\"17537799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CITED2 is a coactivator of PPARα: it interacts directly with PPARα predominantly via the ligand-binding domain (identified by interaction cloning), acts as a dose-dependent transcriptional coactivator of PPARα-dependent reporter genes in the presence of ligands, and also coactivates PPARγ but not PPARβ.\",\n      \"method\": \"cDNA library interaction cloning with bacterially expressed PPARα; GST pull-down; transient transfection reporter assays; stable overexpression/siRNA knockdown in hepatocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction cloning plus direct binding plus functional reporter assays, single lab\",\n      \"pmids\": [\"15051727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CITED2 is upregulated by flow shear (5 dyn/cm²) in human chondrocytes and downregulates MMP-1 and MMP-13 mRNA and enzyme activity. CITED2 associates with p300, displacing Ets-1 from p300, thereby suppressing Ets-1-dependent MMP transcription. TGF-β stimulation promotes both CITED2 expression and its association with p300.\",\n      \"method\": \"Sense/antisense CITED2 overexpression under flow shear; co-immunoprecipitation of CITED2-p300 and p300-Ets-1 complexes; MMP activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function plus Co-IP mechanism, single lab\",\n      \"pmids\": [\"12960175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CITED2 physically interacts with Smad2 and Smad3 (co-IP, mammalian two-hybrid, GST pull-down). p300 enhances the CITED2–Smad3 interaction and transcriptional responses. CITED2 is recruited to the MMP9 promoter upon TGF-β stimulation (ChIP). CITED2 enhances TGF-β-mediated MMP9 upregulation and knockdown of CITED2 attenuates TGF-β-induced MMP9 expression and cell invasion.\",\n      \"method\": \"Co-immunoprecipitation; mammalian two-hybrid; GST pull-down; chromatin immunoprecipitation; siRNA knockdown; invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, two-hybrid, GST pull-down, ChIP, functional invasion assay) in single study\",\n      \"pmids\": [\"16619037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 is required for hepatic gluconeogenesis: it inhibits acetylation of PGC-1α by blocking its interaction with the acetyltransferase GCN5, reducing PGC-1α acetylation and increasing its coactivation of gluconeogenic genes. Glucagon-cAMP-PKA signaling increases hepatic CITED2 abundance; insulin–PI3K–Akt signaling disrupts the CITED2–GCN5 interaction. Loss of hepatic CITED2 suppresses gluconeogenesis in diabetic mice.\",\n      \"method\": \"Conditional knockout mice; co-immunoprecipitation (CITED2-GCN5 interaction); PGC-1α acetylation assay; gluconeogenic gene expression analysis; in vivo glucose production assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined molecular mechanism (Co-IP, acetylation assay) and in vivo metabolic phenotype\",\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 activity while attenuating its activity toward PGC-1α. This CITED2-dependent substrate switch of GCN5 simultaneously promotes epigenetic activation of gluconeogenic gene promoters and PGC-1α-mediated coactivation, thereby triggering gluconeogenesis.\",\n      \"method\": \"In vitro kinase assay (PKA phosphorylation of GCN5); histone acetyltransferase activity assay; ChIP; gluconeogenic gene expression in CITED2-deficient mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase and HAT assays plus ChIP plus in vivo knockout, single lab\",\n      \"pmids\": [\"27874008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CITED2 is required for normal fetal liver hematopoiesis: Cited2−/− fetal liver shows reduced Lin−c-Kit+Sca-1+ cells and progenitors of all lineages, severely impaired colony formation, and compromised primary and secondary transplantation reconstitution of T, B, and myeloid lineages.\",\n      \"method\": \"Cited2 null mouse model; flow cytometry; colony-forming assay; competitive bone marrow transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function null mouse with multiple orthogonal hematopoietic readouts including transplantation\",\n      \"pmids\": [\"17644732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cited2 is selectively and cell-autonomously required for adult hematopoietic stem cell (HSC) maintenance. Conditional deletion of Cited2 causes loss of HSCs and multilineage bone marrow failure. Additional deletion of Ink4a/Arf or Trp53 (p53) restores HSC functionality and rescues mice from bone marrow failure, placing Cited2 upstream of the Ink4a/Arf–p53 axis in HSC maintenance.\",\n      \"method\": \"Conditional knockout (Mx1-Cre); bone marrow transplantation; genetic epistasis with Ink4a/Arf and Trp53 null alleles; flow cytometry\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus genetic epistasis defining pathway, multiple orthogonal readouts, replicated across labs\",\n      \"pmids\": [\"19951693\"],\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 expression of p57 and Hes1 but not Egr1, indicating that CITED2 regulates HSC quiescence through both HIF-1-dependent and HIF-1-independent pathways.\",\n      \"method\": \"Double-conditional knockout (Cited2 and HIF-1α); bone marrow transplantation; flow cytometry; transcriptional profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with defined molecular targets, multiple orthogonal readouts\",\n      \"pmids\": [\"22308296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cited2 controls fibroblast proliferation via the polycomb-group genes Bmi1 and Mel18: Cited2−/− fibroblasts show premature proliferative arrest with increased p16INK4a, p19ARF, and p15INK4b expression and reduced Bmi1/Mel18 levels. Deletion of INK4a/ARF completely rescues proliferative defects of Cited2−/− fibroblasts. Bmi1 and Mel18 retroviruses also rescue proliferation, placing them downstream of Cited2.\",\n      \"method\": \"Cited2 null mouse embryonic fibroblasts; INK4a/ARF genetic rescue; retroviral complementation with CITED2, Bmi1, Mel18\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus retroviral complementation defining pathway order with specific proliferative phenotype\",\n      \"pmids\": [\"14560011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cited2 is a coactivator of HNF4α and is essential for fetal liver development. CITED2 physically interacts with HNF4α and is recruited to HNF4α-responsive promoters (ChIP). In the absence of Cited2, HNF4α binding to its target gene promoters is reduced.\",\n      \"method\": \"Cited2 null mouse fetal liver; co-immunoprecipitation (CITED2–HNF4α); chromatin immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus ChIP in null mouse model establishing direct physical and functional interaction\",\n      \"pmids\": [\"17932483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CITED2 attenuates hypoxic activation of HIF-1α N-terminal transactivation domain (NAD)-dependent genes in addition to C-terminal TAD (CAD)-dependent genes. NAD interacts with both CH1 and CH3 domains of p300; CITED2 blocks NAD binding to CH1 but not CH3. pVHL also inhibits NAD activity by blocking the p300-NAD interaction.\",\n      \"method\": \"Co-immunoprecipitation (NAD-CH1, NAD-CH3 interactions); reporter gene assays for NAD- and CAD-dependent targets; siRNA knockdown\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP domain mapping plus reporter assays, single lab\",\n      \"pmids\": [\"21925214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CITED2 constitutively localizes in the nucleus and interacts with p300, preventing p65 (NF-κB) from binding to p300, impairing p65 acetylation and p65 binding to target promoters. LPS induces CITED2 expression via NF-κB in macrophages, establishing a negative feedback loop. CITED2 also sensitizes cells to TNF-α-induced apoptosis.\",\n      \"method\": \"Subcellular fractionation/nuclear localization imaging; co-immunoprecipitation (CITED2-p300, p65-p300); p65 acetylation assay; ChIP; ectopic expression and knockdown reporter assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IP and functional assays in single lab establishing negative feedback mechanism\",\n      \"pmids\": [\"21098220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CITED2 is degraded via the ubiquitin-proteasome system and is stabilized by proteasome inhibitors. Stabilized CITED2 inhibits HIF-1α C-terminal transactivation domain (CAD) activity and blocks p300 recruitment by HIF-1α, explaining the paradoxical reduction of HIF-1α transcriptional activity upon proteasome inhibition.\",\n      \"method\": \"Proteasome inhibitor treatment (MG132); CITED2 siRNA rescue; co-immunoprecipitation (HIF-1α-p300); reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic rescue with siRNA plus Co-IP, single lab\",\n      \"pmids\": [\"17906695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TGF-β downregulates CITED2 mRNA post-transcriptionally via the Smad pathway (requires Smad4, blocked by Smad7 overexpression), accelerating turnover of Cited2 transcripts. The C-terminal conserved coding region of Cited2 is required for TGF-β-mediated mRNA destabilization. Transcriptional rate is not affected.\",\n      \"method\": \"Nuclear run-on analysis; promoter reporter assay; Smad7 overexpression/Smad4 knockdown; transcript turnover assay with transcription inhibitors; heterologous promoter-driven Cited2 coding sequence constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic approaches distinguishing transcriptional vs post-transcriptional regulation, single lab\",\n      \"pmids\": [\"16675452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CITED2 acts within the WT1/SF1 regulatory pathway in the gonad to increase Sry expression above the threshold required for testis determination. Reducing Wt1 or Sf1 gene dosage in Cited2 mutants produces partial XY sex reversal, and a hypomorphic SryPOS allele causes full sex reversal, placing Sry as a downstream target of the CITED2/WT1/SF1 pathway.\",\n      \"method\": \"Genetic epistasis in mice (Cited2, Wt1, Sf1 compound mutants; SryPOS allele); gene expression analysis of Sry and Sf1 during sex determination\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multi-allele genetic epistasis in vivo with quantitative expression analysis defining pathway order\",\n      \"pmids\": [\"19457926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of Cited2 from heart progenitors (Nkx2-5-Cre) does not alter cardiac development, whereas extra-cardiac deletion establishes that heart defects in Cited2-null embryos arise from failure to establish the left-right body axis. Cited2 is identified as a potentiator of BMP signalling that counteracts initiation of Nodal expression in the left lateral plate mesoderm.\",\n      \"method\": \"Conditional knockout (multiple Cre drivers); epistasis with BMP signaling pathway; gene expression analysis in node and LPM\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional lineage-specific knockout with multiple Cre lines defining extra-cardiac requirement and pathway position\",\n      \"pmids\": [\"21224256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 functions as a molecular switch between TGF-α-induced proliferation and TGF-β-mediated quiescence: upon TGF-α induction, CITED2 is induced by MYC and recruits p300 to promote MYC-p300-mediated transactivation of E2F3, driving G1/S progression. CITED2 also interacts with HDAC1 and potentiates MYC-HDAC1-mediated suppression of p21CIP1. TGF-β downregulates CITED2, abolishing these effects.\",\n      \"method\": \"Co-immunoprecipitation (CITED2-p300, CITED2-HDAC1, MYC-HDAC1 complexes); reporter assays; siRNA knockdown; overexpression; cell cycle analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IP interactions plus functional reporter and phenotypic assays, single lab\",\n      \"pmids\": [\"22814619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CITED2 acts as a coactivator of liver-enriched transcription factor HNF4α for fetal liver development; in neurons, CITED2 is upregulated by DNA damage downstream of Cdk4 and activates PPARγ, which is required for DNA damage-induced neuronal apoptosis. CITED2 overexpression promotes death and CITED2 deficiency protects; Cdk4 blockade prevents CITED2 induction.\",\n      \"method\": \"Gene array plus RT-PCR/Western blot in camptothecin-treated neurons; CITED2 overexpression/knockdown with apoptosis assay; Cdk4 inhibitor; PPARγ reporter assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple gain/loss-of-function experiments defining pathway order (Cdk4→CITED2→PPARγ→apoptosis), single lab\",\n      \"pmids\": [\"18495890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 is recruited to the Oct4 promoter during early embryonic stem cell differentiation (ChIP) and regulates Oct4 expression. Loss of Cited2 delays silencing of pluripotency genes (Oct4, Klf4, Sox2, c-Myc) and impairs cardiomyocyte, hematopoietic, and neuronal differentiation.\",\n      \"method\": \"Cited2 knockout ESCs; chromatin immunoprecipitation (CITED2 at Oct4 promoter); differentiation assays; gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct promoter occupancy plus loss-of-function phenotype, single lab\",\n      \"pmids\": [\"22761414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 is a direct effector of PPARγ in hepatocellular carcinoma: PPARγ activation induces CITED2 expression and is the most prominent PPARγ-bound target gene by ChIP-PCR. CITED2 knockdown increases cell viability and promotes G1-S transition, while ectopic CITED2 suppresses HCC cell growth associated with upregulation of CDK inhibitors and tumor suppressor genes.\",\n      \"method\": \"Chromatin immunoprecipitation (PPARγ at CITED2 promoter); loss- and gain-of-function assays; cell cycle analysis\",\n      \"journal\": \"Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional gain/loss-of-function with cell cycle readout, single lab\",\n      \"pmids\": [\"23212831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXL5 directly interacts with CITED2 and targets it for proteasomal degradation. Depletion of FBXL5 by RNAi increases CITED2 protein levels; overexpression of FBXL5 decreases CITED2 levels in a proteasome-dependent manner, impairs CITED2–CH1(p300) interaction, and enables HIF-1α N-terminal transactivation domain activity.\",\n      \"method\": \"Co-immunoprecipitation (CITED2-FBXL5); RNAi knockdown of FBXL5; proteasome inhibitor rescue; CITED2-CH1 interaction assay in living cells; HIF-1α TAD reporter assay\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional proteasome-dependent degradation assay plus reporter, single lab\",\n      \"pmids\": [\"25956243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Moderate mechanical loading (2.5 MPa, 1 Hz intermittent hydrostatic pressure) upregulates CITED2 in chondrocytes via p38δ phosphorylation. CITED2 suppresses MMP-1 expression by competing with Ets-1 for binding to p300 (demonstrated by competitive binding and transcription assays). In vivo, daily passive joint motion prevents MMP-1 upregulation and cartilage degradation coincident with CITED2 induction.\",\n      \"method\": \"Competitive binding assay (CITED2 vs Ets-1 for p300); transcription assays; in vitro hydrostatic pressure system; in vivo hind-limb immobilization model; p38δ-specific inhibition/phosphorylation analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding assay plus in vitro and in vivo mechanistic experiments, single lab\",\n      \"pmids\": [\"20826544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In nucleus pulposus cells, HIF-2α preferentially regulates CITED2 expression and promoter activity under hypoxia (unlike HIF-1α's predominant role in most other tissues). Forced expression or suppression of CITED2 causes corresponding changes in VEGF expression, establishing CITED2 as a regulator of VEGF in this cell type.\",\n      \"method\": \"HIF-2α/HIF-1α siRNA suppression; gain- and loss-of-function CITED2 constructs; promoter activity assays; VEGF expression measurement\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple constructs establishing mechanistic link, single lab\",\n      \"pmids\": [\"19035510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CITED2 knockdown induces CBP/p300-mediated p53 acetylation at Lys373, decreases p53 ubiquitination, and stabilizes p53 protein, sensitizing cancer cells to cisplatin-induced apoptosis in a p53-dependent manner.\",\n      \"method\": \"shRNA knockdown; p53 acetylation assay (Lys373); p53 ubiquitination assay; cisplatin cytotoxicity in p53-positive vs p53-defective cell lines\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical acetylation/ubiquitination assays plus p53-status-dependent functional comparison, single lab\",\n      \"pmids\": [\"21660965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CITED2 silencing reduces ERCC1 expression and impairs p53-dependent chromatin relaxation (H3K9Ac, H3K14Ac) at the ERCC1 promoter in response to cisplatin. ChIP shows p53 and acetylated histones bind the ERCC1 promoter upon cisplatin treatment in a CITED2/p300-dependent manner, establishing a CITED2/p300/p53/ERCC1 pathway in DNA damage response.\",\n      \"method\": \"shRNA knockdown; chromatin immunoprecipitation (p53, H3K9Ac, H3K14Ac at ERCC1 promoter); ERCC1 reporter; DNA damage comet assay; xenograft model\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with multiple histone marks plus functional DNA repair assay, single lab\",\n      \"pmids\": [\"26384430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 cardiomyocyte-specific knockout (Cited2Nkx) causes ventricular septal defects and compact layer thinning associated with reduced capillary density and 1.5-fold reduction in Vegfa expression. ChIP confirms CITED2 occupancy at the Vegfa promoter in mouse embryonic hearts; CITED2 activates human VEGFA promoter cooperatively with TFAP2 in transient transfection assays.\",\n      \"method\": \"Cardiomyocyte-specific conditional knockout; histology and MRI; chromatin immunoprecipitation (CITED2 at Vegfa promoter); transient transfection reporter assay\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP and functional reporter assay establishing direct regulation of Vegfa\",\n      \"pmids\": [\"22504313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cited2 and Tcfap2c complex is present at the Cebpa promoter in E18.5 lungs (ChIP) and activates Cebpa transcription. Loss of Cited2 reduces Cebpa expression in fetal lungs and impairs alveolar epithelial cell differentiation.\",\n      \"method\": \"Cited2 null mouse lung; chromatin immunoprecipitation (Cited2, Tcfap2c at Cebpa promoter); gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function null mouse with specific molecular target, single lab\",\n      \"pmids\": [\"18358466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CITED2 acts as a molecular chaperone guiding PRMT5 and p300 to nucleolin, thereby activating nucleolin. The CITED2-nucleolin axis stimulates cell migration through epithelial-mesenchymal transition and promotes prostate cancer metastasis in a xenograft model.\",\n      \"method\": \"Co-immunoprecipitation (CITED2-PRMT5, CITED2-p300, CITED2-nucleolin); functional migration/invasion assays; xenograft mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing ternary complex plus functional in vivo xenograft, single lab\",\n      \"pmids\": [\"30291252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CITED2 deficiency in macrophages elevates HIF-1α protein stability and proinflammatory cytokine/chemokine gene expression; overexpression of Egln3 (a prolyl hydroxylase) or HIF-1α inhibition completely reverses elevated proinflammatory gene expression in Cited2-deficient macrophages. CITED2 also promotes PPARγ activation and anti-inflammatory gene expression.\",\n      \"method\": \"Myeloid-specific conditional knockout; Egln3 overexpression rescue; HIF-1α inhibition rescue; gain- and loss-of-function reporter assays; endotoxin sepsis model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus genetic/pharmacologic rescue defining pathway, in vivo sepsis model\",\n      \"pmids\": [\"29203644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CITED2 deficiency in macrophages elevates STAT1 transcriptional activity and IRF1 expression; siRNA-mediated knockdown of IRF1 completely reverses elevated proinflammatory gene expression in CITED2-deficient macrophages. Myeloid-CITED2-deficient mice on Apoe−/− background develop larger atherosclerotic lesions.\",\n      \"method\": \"Myeloid-specific conditional knockout; ChIP (STAT1 enrichment on IRF1 promoter); IRF1 siRNA rescue; atherosclerosis lesion quantification\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus ChIP plus epistatic siRNA rescue defining STAT1-IRF1 pathway, in vivo atherosclerosis model\",\n      \"pmids\": [\"34365659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CITED2 is recruited to the IKKα promoter in breast cancer cells (ChIP), directly regulating IKKα expression. CITED2 knockdown reduces IKKα and several NF-κB target genes; restoration of IKKα rescues the invasive ability lost upon CITED2 knockdown, demonstrating a CITED2→IKKα→NF-κB axis in breast cancer metastasis.\",\n      \"method\": \"Chromatin immunoprecipitation (CITED2 at IKKα promoter); shRNA knockdown; IKKα rescue experiment; invasion assay; xenograft model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus epistatic rescue experiment with functional invasion readout, single lab\",\n      \"pmids\": [\"27216153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CITED2 is recruited to the CCL20 promoter in MDA-MB-231 breast cancer cells (ChIP), and CITED2 knockdown reduces CCL20 expression and attenuates macrophage recruitment both in vitro and in orthotopic tumors.\",\n      \"method\": \"Chromatin immunoprecipitation (CITED2 at CCL20 promoter); shRNA knockdown; Transwell macrophage recruitment assay; orthotopic xenograft\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional macrophage recruitment assay in vitro and in vivo, single lab\",\n      \"pmids\": [\"29399152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CITED2 cooperates physically with ISL1 (co-immunoprecipitation) and together they promote cardiomyocyte differentiation from mouse ESCs. Loss of Cited2 impairs early mesoderm and cardiogenic transcription factor expression (Isl1, Gata4, Tbx5); CITED2 recombinant protein rescues cardiogenic defects in Cited2-depleted cells.\",\n      \"method\": \"Co-immunoprecipitation (CITED2-ISL1); Cited2 knockdown in ESC differentiation; recombinant protein rescue; cardiac differentiation assay\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus loss-of-function and protein rescue, single lab\",\n      \"pmids\": [\"27818139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cited2 directly targets Nanog, Tbx3, and Klf4 in mouse ESCs and is required for their expression; constitutive Nanog expression partially rescues the proliferation, survival, and self-renewal defects caused by Cited2 depletion, positioning Nanog downstream of Cited2 in the pluripotency network.\",\n      \"method\": \"Acute Cited2 deletion in ESCs; ChIP (CITED2 at Nanog/Tbx3/Klf4 loci); Nanog overexpression rescue; self-renewal assay\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus epistatic rescue placing Nanog downstream of CITED2, single lab\",\n      \"pmids\": [\"25377420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cited2 is recruited to the hexokinase 1 (HK1) gene promoter (ChIP) in mouse ESCs to regulate HK1 transcription, coordinating glucose metabolism. Cited2 knockout ESCs show enhanced glycolysis, reduced glucose oxidation, abnormal mitochondrial morphology, and decreased ATP, correlated with defective differentiation under hypoxia.\",\n      \"method\": \"Cited2 knockout ESCs; chromatin immunoprecipitation (CITED2 at HK1 promoter); metabolic assays (glycolysis, oxygen consumption, ATP); differentiation assay under hypoxia\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus comprehensive metabolic phenotyping in KO cells, single lab\",\n      \"pmids\": [\"24265312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cited2 deficiency in adult HSCs reduces expression of Pdk2, Pdk4, LDHB, and LDHD, leading to decreased glycolysis, elevated reactive oxygen species, and increased mitochondrial activity. Inhibition of PI3K/Akt (but not mTORC1) partially restores Pdk4 expression in Cited2-deficient HSCs.\",\n      \"method\": \"Conditional knockout HSCs; metabolic assays (glycolysis, mitochondrial activity, ROS); PI3K/Akt and mTORC1 inhibitors; gene expression analysis\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pharmacologic pathway dissection and metabolic readouts, single lab\",\n      \"pmids\": [\"24083546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Indoxyl sulfate upregulates CITED2 through post-transcriptional mRNA stabilization involving the ERK1/2 pathway (not HIF-1α protein level changes), thereby functionally impairing HIF-1α C-terminal transactivation domain activity and suppressing HIF-1 target genes.\",\n      \"method\": \"mRNA stability assay; ERK1/2 pathway inhibition; HIF-1α CTAD reporter; protein and mRNA quantification in HK-2 cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay plus pathway inhibition identifying ERK1/2-dependent mechanism, single lab\",\n      \"pmids\": [\"23792300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CITED2 is phosphorylated by MAPK1 (ERK2) in vitro at T166 within the SRJ domain. MAPK1 activation enhances the TFAP2 coactivation function of CITED2 but not of the T166N mutant, establishing T166 as a regulatory phosphorylation site for CITED2 coactivation activity.\",\n      \"method\": \"In vitro kinase assay (MAPK1 phosphorylation of CITED2); T166N point mutation; TFAP2 coactivation reporter assay; knock-in mouse (no morphological phenotype with T166N or ΔSRJ alleles)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional reporter, single lab; in vivo knock-in did not produce phenotype\",\n      \"pmids\": [\"23082118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CITED2 is required for expression of key HSC regulators GATA2, MCL-1, and PTEN. Hematopoietic-specific MCL-1 overexpression partially rescues the Cited2-deficient HSC pool and reconstitution potential. Cited2;Pten compound heterozygotes show decreased HSC numbers and failed reconstitution, placing PTEN downstream of CITED2.\",\n      \"method\": \"Hematopoietic-specific conditional knockout; MCL-1 transgenic rescue; Cited2;Pten compound heterozygotes; bone marrow transplantation; transcriptomics/GSEA\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus genetic rescue (MCL-1 transgene) plus compound heterozygote epistasis defining GATA2/MCL-1/PTEN as direct targets\",\n      \"pmids\": [\"34715054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CITED2 is distinctively expressed in junctional zone and invasive trophoblast cells in rat placenta and in extravillous trophoblast (EVT) cell columns in human placenta. Homozygous Cited2 deletion disrupts the junctional zone, delays intrauterine trophoblast invasion, and compromises trophoblast plasticity, establishing CITED2 as a conserved regulator of deep hemochorial placentation.\",\n      \"method\": \"Cited2 null rat and human trophoblast loss-of-function; immunofluorescence localization; trophoblast invasion assays; EVT lineage differentiation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cross-species loss-of-function (rat null + human trophoblast) with direct localization and functional invasion readout\",\n      \"pmids\": [\"36626551\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CITED2 is a nuclear, intrinsically disordered transcriptional co-regulator that binds with high affinity to the CH1/TAZ1 domain of CBP/p300 through an LPXL motif, competitively displacing HIF-1α and thereby acting as a negative feedback regulator of hypoxic gene expression; it simultaneously co-activates transcription factors including TFAP2A/B/C, HNF4α, PPARα/γ, Smad2/3, estrogen receptor, and ISL1 by bridging them to p300/CBP, and it modulates the GCN5 acetyltransferase substrate switch to control PGC-1α-dependent gluconeogenesis, regulates NF-κB and STAT1-IRF1 inflammatory signalling in macrophages, controls fibroblast and HSC proliferation via Bmi1/Mel18-INK4a/ARF-p53, drives left-right patterning through a Nodal→Pitx2c pathway in concert with TFAP2, and is subject to regulation by post-translational modifications including MAPK1-mediated phosphorylation at T166 and FBXL5-directed proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CITED2 is a nuclear, intrinsically disordered transcriptional co-regulator that operates principally by competing for the CH1/TAZ1 domain of the coactivators CBP/p300, thereby reprogramming which transcription factors gain access to p300's acetyltransferase activity [#0, #1]. Its transactivation domain folds upon binding the zinc-containing CH1 scaffold through an 'LPXL' hot spot that overlaps the HIF-1\\u03b1 binding surface, allowing CITED2 to displace HIF-1\\u03b1 from p300 and act as a negative-feedback brake on hypoxic gene expression \\u2014 a loop induced by FOXO3a and HIF-1 itself, and that limits both C-terminal and N-terminal HIF-1\\u03b1 transactivation domain activity [#0, #1, #4, #6, #18]. Conversely, CITED2 bridges p300/CBP to a broad set of sequence-specific factors to activate transcription, most prominently the TFAP2 family, with which it forms a trimeric p300\\u2013CITED2\\u2013TFAP2 complex requiring p300 HAT activity [#2, #3]; it likewise co-activates HNF4\\u03b1, PPAR\\u03b1/\\u03b3, Smad2/3, and ISL1 and occupies target promoters including Pitx2c, Vegfa, Cebpa, Oct4, and Nanog [#5, #8, #10, #17, #33, #34, #40, #41]. Through these activities CITED2 controls left-right body-axis establishment via a BMP-counteracting Nodal\\u2192Pitx2c pathway [#5, #23], adrenal and gonadal specification via the WT1/SF1 axis [#7, #22], fetal and adult hematopoietic stem cell maintenance upstream of the Ink4a/ARF\\u2013p53 axis and GATA2/MCL-1/PTEN [#13, #14, #16, #46], hepatic gluconeogenesis by modulating the GCN5 acetyltransferase substrate switch on PGC-1\\u03b1 [#11, #12], and inflammatory signalling in macrophages by restraining HIF-1\\u03b1- and STAT1-IRF1-driven proinflammatory programs [#36, #37]. CITED2 abundance and activity are tuned by post-translational control, including FBXL5-directed proteasomal degradation and MAPK1 phosphorylation at T166 in the SRJ domain that enhances TFAP2 coactivation [#28, #45]. Loss-of-function mouse and rat models tie these molecular roles to cardiac, neural crest, hematopoietic, and placental developmental defects [#2, #33, #47].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the first defined molecular partner and developmental role for CITED2 by showing it co-activates the TFAP2 transcription factor family, framing it as a transcriptional coactivator rather than an orphan protein.\",\n      \"evidence\": \"Co-IP, transactivation rescue in Cited2-null fibroblasts, and Cited2 null mouse phenotyping\",\n      \"pmids\": [\"11694877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how CITED2 bridges TFAP2 to the general transcription machinery\", \"Mechanism connecting molecular defect to the diverse null phenotypes unaddressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined CITED2's signature activity as a negative regulator of HIF-1\\u03b1, explaining how it dampens hypoxic gene expression in vivo.\",\n      \"evidence\": \"Cited2 null mice with qRT-PCR of HIF-1\\u03b1 target genes in hearts and fibroblasts under hypoxia\",\n      \"pmids\": [\"12149478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HIF-1\\u03b1 displacement not yet shown\", \"Whether inhibition extends beyond C-terminal HIF-1\\u03b1 transactivation unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Solved the structural mechanism of competition, showing the disordered CITED2 TAD folds on the p300/CBP CH1 domain and outcompetes HIF-1\\u03b1 at an overlapping LPXL hot spot.\",\n      \"evidence\": \"NMR solution structures of the CITED2 TAD\\u2013CH1/TAZ1 complex, competitive binding assays, and LPEL mutagenesis with in vivo p300 binding\",\n      \"pmids\": [\"12778114\", \"14594809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how CITED2 selectively recruits versus displaces partners at the same surface\", \"Affinity differences across the many CITED2-CBP-dependent factors not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed CITED2 nucleates a trimeric p300\\u2013CITED2\\u2013TFAP2 complex whose coactivation depends on p300 HAT activity, and extended the displacement principle to Ets-1, linking CITED2 to MMP suppression under mechanical/TGF-\\u03b2 cues.\",\n      \"evidence\": \"Co-IP, mammalian two-hybrid, reporter assays with a HAT-deficient p300 mutant, and competitive p300-binding assays in chondrocytes\",\n      \"pmids\": [\"12586840\", \"12960175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylation substrates relevant to TFAP2 targets not identified\", \"Generality of Ets-1 displacement across cell types untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed CITED2 upstream of a polycomb\\u2013INK4a/ARF axis controlling proliferation, establishing a developmentally relevant growth-control pathway.\",\n      \"evidence\": \"Cited2-null MEFs with INK4a/ARF genetic rescue and retroviral Bmi1/Mel18 complementation\",\n      \"pmids\": [\"14560011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets linking CITED2 to Bmi1/Mel18 not defined\", \"Whether effect is p300-dependent unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected CITED2 to body-axis patterning through a Nodal\\u2192Pitx2c pathway acting with TFAP2 at the Pitx2c promoter.\",\n      \"evidence\": \"ChIP from embryonic hearts, transient reporter assays, and Cited2-null gene expression analysis\",\n      \"pmids\": [\"15475956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CITED2 initiates left-sided Nodal expression not resolved\", \"Cardiac versus extra-cardiac origin of defects unclear at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Broadened the coactivator repertoire to nuclear receptors by demonstrating direct, ligand-dependent coactivation of PPAR\\u03b1 and PPAR\\u03b3.\",\n      \"evidence\": \"Interaction cloning, GST pull-down, reporter assays, and overexpression/knockdown in hepatocytes\",\n      \"pmids\": [\"15051727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without structural confirmation\", \"PPAR target genes in vivo not defined here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified CITED2 as a Smad2/3 partner and showed it is itself post-transcriptionally downregulated by TGF-\\u03b2, defining a regulated CITED2-TGF-\\u03b2 node controlling MMP9 and invasion.\",\n      \"evidence\": \"Co-IP, two-hybrid, GST pull-down, ChIP at MMP9, knockdown invasion assays, and transcript turnover analysis\",\n      \"pmids\": [\"16619037\", \"16675452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding factor mediating TGF-\\u03b2-driven mRNA destabilization unidentified\", \"Reconciliation of CITED2 promoting MMP9 here yet suppressing MMP-1/13 elsewhere unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established CITED2 within feedback and developmental gene circuits: a FOXO3a/HIF-1-induced antiapoptotic feedback loop, a coactivator of HNF4\\u03b1 for fetal liver, a WT1/SF1-pathway component for adrenal specification, and a requirement for fetal liver hematopoiesis.\",\n      \"evidence\": \"Reporter and knockdown assays under hypoxia; Co-IP and ChIP in null livers; mouse genetic epistasis; transplantation assays\",\n      \"pmids\": [\"18158893\", \"17932483\", \"17537799\", \"17644732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these roles share the common p300-bridging mechanism not directly tested across contexts\", \"Direct CITED2 targets in hematopoietic progenitors not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a cell-autonomous requirement for CITED2 in adult HSC maintenance acting upstream of the Ink4a/ARF\\u2013p53 axis, and extended the WT1/SF1 pathway to Sry-dependent testis determination.\",\n      \"evidence\": \"Conditional knockout with Ink4a/Arf and Trp53 epistasis and transplantation; multi-allele genetic epistasis with Wt1/Sf1/Sry\",\n      \"pmids\": [\"19951693\", \"19457926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional link between CITED2 and Ink4a/Arf repression not shown\", \"Molecular mechanism setting Sry expression threshold unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Generalized the p300-displacement mechanism to NF-\\u03baB p65 and resolved that CITED2 cardiac defects arise extra-cardiacally from failed left-right axis establishment, with CITED2 acting as a BMP potentiator.\",\n      \"evidence\": \"Co-IP and p65 acetylation/ChIP assays in macrophages; lineage-specific conditional knockouts with BMP epistasis\",\n      \"pmids\": [\"21098220\", \"21224256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo NF-\\u03baB targets restrained by CITED2 not yet mapped\", \"Mechanistic link between BMP potentiation and Nodal suppression incomplete\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expanded HIF inhibition to the N-terminal transactivation domain and revealed that CITED2 levels also tune p53 acetylation/stability and drug sensitivity through p300.\",\n      \"evidence\": \"Co-IP domain mapping and reporter assays; shRNA knockdown with p53 acetylation/ubiquitination and cisplatin cytotoxicity assays\",\n      \"pmids\": [\"21925214\", \"21660965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both single-lab; how CITED2 selectively gates p53 versus HIF access to p300 unclear\", \"In vivo relevance of CITED2-p53 axis not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a major metabolic role: CITED2 controls hepatic gluconeogenesis by blocking GCN5-mediated PGC-1\\u03b1 acetylation, integrating glucagon/insulin signalling, and directly regulates Vegfa with TFAP2 in the developing heart.\",\n      \"evidence\": \"Conditional knockout mice, Co-IP, PGC-1\\u03b1 acetylation and glucose-production assays; cardiomyocyte-specific knockout with ChIP and reporter at Vegfa\",\n      \"pmids\": [\"22426420\", \"22504313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How signalling-driven changes in CITED2 abundance are achieved mechanistically not fully resolved\", \"Coordination of metabolic versus coactivator roles within the same cell unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Implicated CITED2 in pluripotency and cell-cycle control, occupying the Oct4 promoter during ESC differentiation and acting as a MYC/p300 versus HDAC1 switch between proliferation and quiescence; also identified it as a PPAR\\u03b3 effector tumor suppressor and a Cdk4\\u2192CITED2\\u2192PPAR\\u03b3 neuronal apoptosis mediator.\",\n      \"evidence\": \"ChIP and knockout ESC differentiation; Co-IP of CITED2-p300/HDAC1/MYC with cell-cycle assays; PPAR\\u03b3 ChIP and gain/loss-of-function; neuronal apoptosis assays\",\n      \"pmids\": [\"22761414\", \"22814619\", \"23212831\", \"18495890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context determining pro- versus anti-proliferative outcome not defined\", \"All single-lab with limited cross-validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked CITED2 to cellular metabolism by direct promoter regulation of glycolytic genes (HK1) in ESCs and metabolic gene programs (Pdk2/4, LDH) in HSCs, coupling its transcriptional role to glucose handling and ROS control.\",\n      \"evidence\": \"ChIP and metabolic phenotyping in knockout ESCs and conditional-knockout HSCs with PI3K/Akt inhibition; ERK1/2-dependent mRNA stabilization in renal cells\",\n      \"pmids\": [\"24265312\", \"24083546\", \"23792300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether metabolic gene regulation is direct p300-bridged coactivation untested\", \"Single-lab metabolic readouts\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined an FBXL5-directed proteasomal degradation route controlling CITED2 abundance and HIF-1\\u03b1 access to p300, and placed CITED2/p300 upstream of p53-dependent ERCC1 chromatin remodeling in DNA damage response.\",\n      \"evidence\": \"Co-IP, RNAi, proteasome-dependent degradation and CITED2-CH1 interaction assays; ChIP of p53 and histone acetylation at ERCC1 with DNA-repair assays\",\n      \"pmids\": [\"25956243\", \"26384430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron and ubiquitination sites on CITED2 not mapped\", \"Both single-lab without reciprocal validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined regulatory inputs and outputs: established MAPK1 phosphorylation at T166 as a tunable enhancer of TFAP2 coactivation, demonstrated a GCN5 substrate-switch mechanism for gluconeogenesis, and identified CITED2-driven IKK\\u03b1/NF-\\u03baB and CCL20 programs in breast cancer alongside cooperation with ISL1 in cardiogenesis.\",\n      \"evidence\": \"In vitro kinase assays with T166N mutant; PKA/GCN5 kinase and HAT assays with ChIP; ChIP and rescue/invasion/macrophage-recruitment assays; Co-IP with ISL1 and ESC cardiac differentiation\",\n      \"pmids\": [\"23082118\", \"27874008\", \"27216153\", \"29399152\", \"27818139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"T166N knock-in produced no morphological phenotype, leaving physiological importance of this site uncertain\", \"Cancer-promoting versus tumor-suppressing roles of CITED2 not reconciled mechanistically\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated CITED2 restrains macrophage inflammation by limiting HIF-1\\u03b1 stability and promoting PPAR\\u03b3 activity, and identified a chaperone-like role guiding PRMT5/p300 to activate nucleolin in cancer metastasis.\",\n      \"evidence\": \"Myeloid-specific knockout with Egln3/HIF-1\\u03b1 rescue and sepsis model; Co-IP of CITED2-PRMT5/p300/nucleolin with migration and xenograft assays\",\n      \"pmids\": [\"29203644\", \"30291252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether nucleolin chaperone role uses the same CH1-binding surface unknown\", \"Direct CITED2 control of HIF-1\\u03b1 prolyl-hydroxylase pathway not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified additional macrophage and HSC effectors of CITED2, defining a STAT1-IRF1 inflammatory axis and GATA2/MCL-1/PTEN as required HSC targets with in vivo disease relevance.\",\n      \"evidence\": \"Myeloid conditional knockout with ChIP and IRF1 siRNA rescue plus atherosclerosis model; hematopoietic conditional knockout with MCL-1 transgenic rescue and Pten compound heterozygote epistasis\",\n      \"pmids\": [\"34365659\", \"34715054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GATA2/MCL-1/PTEN are direct CITED2/p300 transcriptional targets not fully shown\", \"Integration of metabolic and survival programs in HSCs unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended CITED2's developmental requirement to placentation, identifying it as a conserved regulator of trophoblast invasion and junctional-zone integrity.\",\n      \"evidence\": \"Cited2 null rat and human trophoblast loss-of-function with localization and invasion/EVT differentiation assays\",\n      \"pmids\": [\"36626551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets driving trophoblast invasion not defined\", \"Whether the role depends on HIF competition or TFAP2 coactivation unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CITED2 selects between displacing (HIF-1\\u03b1, p65, Ets-1) and recruiting (TFAP2, HNF4\\u03b1, nuclear receptors, ISL1) factors at the same p300/CBP CH1 surface, and what determines its context-specific pro- versus anti-proliferative and pro- versus anti-tumor outcomes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling competitive inhibition and coactivation at CH1\", \"Cell-type determinants of opposing growth outcomes undefined\", \"Quantitative affinity hierarchy among CITED2-CBP-dependent partners not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 5, 8, 17, 33]},\n      {\"term_id\": \"GO:0003713\", \"supporting_discovery_ids\": [2, 8, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 18, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 6, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 5, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 7, 22, 23, 33, 47]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 36, 37]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 12, 42, 43]}\n    ],\n    \"complexes\": [\n      \"p300/CBP\\u2013CITED2\\u2013TFAP2 trimeric complex\"\n    ],\n    \"partners\": [\n      \"EP300\",\n      \"CREBBP\",\n      \"TFAP2A\",\n      \"HIF1A\",\n      \"HNF4A\",\n      \"SMAD3\",\n      \"ISL1\",\n      \"FBXL5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}