Affinage

CITED2

Cbp/p300-interacting transactivator 2 · UniProt Q99967

Length
270 aa
Mass
28.5 kDa
Annotated
2026-04-28
100 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CITED2 is an intrinsically disordered nuclear transcriptional co-regulator that modulates gene expression by bridging sequence-specific transcription factors to the acetyltransferase p300/CBP and by competitively displacing other p300/CBP-dependent activators from the CH1 (TAZ1) domain. Its transactivation domain folds upon binding to TAZ1 via a conserved LPEL motif, occupying a partially overlapping surface used by HIF-1α to effect potent competitive inhibition of HIF-1-dependent transcription — a mechanism validated structurally, genetically, and in vivo across cardiac development, hematopoietic stem cell maintenance, macrophage inflammation, and lens morphogenesis (PMID:12778114, PMID:12149478, PMID:19951693, PMID:29203644). Simultaneously, CITED2 acts as a positive co-activator by recruiting p300/CBP to TFAP2, HNF4α, Smad2/3, WT1/SF-1, and MYC at target promoters including Pitx2c, Vegfa, Sry, and E2F3, and it modulates hepatic gluconeogenesis by blocking GCN5-mediated PGC-1α acetylation in a PKA-dependent signaling module (PMID:12586840, PMID:15475956, PMID:17932483, PMID:22426420, PMID:22814619). CITED2 also suppresses NF-κB-p65 and STAT1-IRF1 signaling by sequestering p300, establishing anti-inflammatory negative feedback loops in macrophages relevant to endotoxemia and atherosclerosis (PMID:21098220, PMID:34365659).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 High

    The initial question was whether CITED2 had transcription factor partners beyond p300/CBP; the discovery that CITED2 physically interacts with and is required for TFAP2-dependent transactivation, combined with the severe Cited2-null phenotype, established it as a co-activator essential for cardiac, neural crest, and adrenal development.

    Evidence Co-IP, reporter assays, and Cited2 knockout mouse with lethal cardiac malformations and adrenal agenesis

    PMID:11694877

    Open questions at the time
    • Structural basis of the CITED2–TFAP2 interface was not defined
    • Whether cardiac defects were cell-autonomous was unknown
  2. 2002 High

    This established the in vivo consequence of CITED2's competition with HIF-1α for p300/CBP: loss of Cited2 derepressed HIF-1 target genes in embryonic hearts and fibroblasts, confirming CITED2 as a physiological negative regulator of HIF-1 transcriptional activity.

    Evidence Cited2 knockout mouse with quantitative RT-PCR of HIF-1α target genes under hypoxia

    PMID:12149478

    Open questions at the time
    • Mechanism of competitive displacement was structurally undefined at this point
    • Whether HIF-1 derepression caused the cardiac defects was untested
  3. 2003 High

    Two independent NMR structures resolved how CITED2's intrinsically disordered TAD folds upon binding to the TAZ1 (CH1) domain of p300/CBP and identified the conserved LPEL motif as the critical contact that overlaps with the HIF-1α binding surface, providing the atomic basis for competitive displacement.

    Evidence NMR solution structures of CITED2 TAD–p300 CH1 complex, mutagenesis of LPEL motif, in vivo co-IP

    PMID:12778114 PMID:14594809

    Open questions at the time
    • Kinetic parameters of displacement were not measured experimentally
    • How CITED2 simultaneously co-activates TFAP2 while occupying the same CH1 domain was unclear
  4. 2003 High

    The ternary complex model was established: p300, TFAP2, and CITED2 form a physical complex in vivo, with CITED2 bridging TFAP2 to p300 in a HAT activity-dependent manner, resolving the question of how a co-activator lacking DNA-binding activity enhances transcription.

    Evidence Co-IP from U2-OS cells, mammalian two-hybrid, HAT-dead p300 mutant

    PMID:12586840

    Open questions at the time
    • Whether this ternary model generalizes to other CITED2-dependent TF complexes was untested
  5. 2003 High

    CITED2 was placed upstream of polycomb-group gene regulation (Bmi1/Mel18) and Ink4a/ARF, explaining the premature senescence of Cited2-null fibroblasts and foreshadowing its role in stem cell maintenance.

    Evidence Retroviral complementation and Ink4a/ARF genetic deletion in Cited2−/− fibroblasts

    PMID:14560011

    Open questions at the time
    • Direct transcriptional mechanism linking CITED2 to Bmi1/Mel18 was not defined
    • Whether the same pathway operates in HSCs was unknown
  6. 2004 High

    CITED2 and TFAP2 were shown to activate the Pitx2c promoter (by ChIP), placing CITED2 in the Nodal→Pitx2c left-right patterning pathway and explaining the laterality defects in Cited2-null embryos.

    Evidence ChIP in embryonic hearts, in situ hybridization in Cited2 knockout, reporter assay

    PMID:15475956

    Open questions at the time
    • Whether CITED2 acts directly in the node or lateral plate mesoderm was unresolved
  7. 2006 High

    Multiple new co-activation partnerships and a post-transcriptional regulatory mechanism were defined: CITED2 co-activates Smad2/3 at the MMP9 promoter upon TGF-β stimulation, and TGF-β also downregulates Cited2 mRNA post-transcriptionally via Smad4-dependent mRNA destabilization, revealing a complex TGF-β–CITED2 regulatory circuit.

    Evidence Co-IP, GST pulldown, mammalian two-hybrid for Smad interaction; nuclear run-on and mRNA stability assays for post-transcriptional regulation

    PMID:16619037 PMID:16675452

    Open questions at the time
    • The RNA element mediating Cited2 mRNA destabilization was mapped only to the C-terminal coding region
  8. 2006 High

    Genetic rescue of Cited2-null cardiac defects by HIF-1α haploinsufficiency provided definitive in vivo evidence that excess HIF-1 activity accounts for many of the cardiac malformations, validating the competitive displacement model at the organismal level.

    Evidence Cited2/HIF-1α compound mutant mouse with cardiac histology, MRI, and gene expression

    PMID:17022961

    Open questions at the time
    • Not all phenotypes were rescued, indicating HIF-1-independent CITED2 functions in cardiac development
  9. 2007 High

    CITED2 was established as a critical co-activator of WT1 and SF-1 to regulate adrenal and gonadal development, with compound mutant analysis showing dosage-sensitive control of Sf-1 expression — and separately, HNF4α coactivation was defined in fetal liver, broadening the portfolio of CITED2's tissue-specific TF partnerships.

    Evidence Cited2/Wt1/Sf-1 compound mutant genetics; co-IP and ChIP for HNF4α in fetal liver with Cited2 KO

    PMID:17537799 PMID:17932483

    Open questions at the time
    • Whether CITED2 directly bridges WT1 and p300 at Sf-1 promoters was not shown by ChIP
  10. 2007 High

    FOXO3a-mediated induction of CITED2 during hypoxia established a negative feedback loop limiting HIF-1 pro-apoptotic target gene expression, integrating CITED2 into the FOXO3a survival signaling network.

    Evidence Reporter assays and loss-of-function in fibroblasts and breast cancer cells

    PMID:18158893

    Open questions at the time
    • Whether this loop operates in vivo in tumor hypoxia was not tested
  11. 2009 High

    Conditional deletion in adult mice revealed that CITED2 is essential cell-autonomously for HSC maintenance; concurrent Ink4a/Arf or Trp53 deletion rescued HSC function, connecting CITED2's earlier fibroblast senescence pathway to adult stem cell biology.

    Evidence Conditional Cre-mediated KO, bone marrow transplantation, genetic epistasis with Ink4a/Arf and Trp53

    PMID:19951693

    Open questions at the time
    • Direct transcriptional targets of CITED2 in HSCs were not comprehensively identified
    • How CITED2 regulates p53 at the molecular level was unclear
  12. 2010 High

    CITED2's mechanism as a competitive inhibitor was extended to NF-κB signaling: nuclear CITED2 sequesters p300 from p65, impairing p65 acetylation and DNA binding, while LPS induces CITED2 via NF-κB itself, forming a negative feedback loop in macrophages.

    Evidence Co-IP, ChIP, reporter assay, siRNA knockdown and overexpression in LPS-stimulated macrophages

    PMID:21098220

    Open questions at the time
    • Whether this mechanism accounts for CITED2's anti-inflammatory function in vivo was not tested at this point
  13. 2012 High

    A metabolic regulatory function was uncovered: CITED2 blocks GCN5-mediated PGC-1α acetylation to enhance gluconeogenic gene expression during fasting, with CITED2 abundance itself regulated by glucagon-cAMP-PKA signaling and opposed by insulin-PI3K-Akt signaling.

    Evidence Co-IP, mouse genetic model, reporter assays, pharmacological PI3K-Akt inhibition

    PMID:22426420

    Open questions at the time
    • Whether CITED2 directly interacts with GCN5 or acts through an intermediary was not fully resolved
  14. 2012 High

    In HSCs, HIF-1α deletion partially but not completely rescued Cited2-deficiency phenotypes, genetically dissecting HIF-1-dependent (quiescence genes p57, Hes1) from HIF-1-independent (Egr1) functions of CITED2 in stem cell maintenance.

    Evidence Conditional double-knockout (Cited2/HIF-1α), flow cytometry, bone marrow transplantation

    PMID:22308296

    Open questions at the time
    • Identity of the HIF-1-independent pathway mediating Egr1 regulation was unknown
  15. 2012 Medium

    CITED2 was shown to interact with MYC and recruit p300 to transactivate E2F3 for G1/S progression, while also potentiating MYC-HDAC1-mediated repression of p21, revealing dual co-activator and co-repressor roles in cell cycle control.

    Evidence Co-IP, ChIP, siRNA knockdown, reporter assay

    PMID:22814619

    Open questions at the time
    • Whether CITED2-MYC interaction is direct or p300-mediated was not fully resolved
    • In vivo relevance for tumorigenesis was not demonstrated
  16. 2016 High

    The GCN5-CITED2-PKA module was further refined: PKA phosphorylates GCN5 in a CITED2-dependent manner, switching GCN5 substrate preference from PGC-1α to histones at gluconeogenic promoters, achieving simultaneous epigenetic activation and coactivator deacetylation.

    Evidence In vitro kinase assay, HAT activity assay, co-IP, mouse genetic models

    PMID:27874008

    Open questions at the time
    • The phosphorylation site on GCN5 was not mapped
    • Whether this module operates in non-hepatic tissues was untested
  17. 2016 High

    Tissue-specific conditional knockouts clarified that CITED2's role in cardiac outflow tract patterning is extra-cardiac (acting via left-right axis), while cardiomyocyte-specific deletion revealed a separate, cell-autonomous requirement for CITED2–TFAP2 co-activation of Vegfa in myocardial vascularization.

    Evidence Cardiac-specific vs. cardiomyocyte-specific conditional KO, ChIP at Vegfa promoter, MRI, vessel morphometry

    PMID:21224256 PMID:22504313

    Open questions at the time
    • Whether CITED2 regulates Vegfa independently of HIF-1α in cardiomyocytes was not addressed
  18. 2021 High

    CITED2 deficiency in macrophages was shown to elevate STAT1-IRF1 pro-inflammatory signaling by increasing STAT1 enrichment at the IRF1 promoter, with myeloid CITED2 deletion exacerbating atherosclerosis, demonstrating a new anti-inflammatory axis beyond NF-κB and HIF-1.

    Evidence Myeloid conditional KO on Apoe−/− background, ChIP for STAT1 at IRF1, IRF1 siRNA rescue, transcriptomics

    PMID:34365659

    Open questions at the time
    • Whether CITED2 directly competes with STAT1 for p300 or acts through another mechanism was not determined
    • Relative contribution of HIF-1, NF-κB, and STAT1-IRF1 pathways to the atherosclerosis phenotype was not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the full structural basis of how CITED2 simultaneously co-activates diverse transcription factors while competitively inhibiting others at the same p300 CH1 domain, the identity and regulation of E3 ligases beyond FBXL5 controlling CITED2 turnover, and whether the GCN5-CITED2-PKA gluconeogenic module operates in metabolic tissues beyond liver.
  • No full ternary structure of CITED2–p300–any partner TF exists
  • CITED2 ubiquitination sites and comprehensive E3 ligase regulation remain incomplete
  • Comprehensive ChIP-seq/CUT&RUN genome-wide occupancy studies in primary tissues are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0098772 molecular function regulator activity 8 GO:0060090 molecular adaptor activity 5
Localization
GO:0005634 nucleus 7
Pathway
R-HSA-74160 Gene expression (Transcription) 11 R-HSA-1266738 Developmental Biology 9 R-HSA-162582 Signal Transduction 7 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3
Partners
CREBBPEP300HIF1AHNF4AKAT2ASMAD3TFAP2AWT1
Complex memberships
GCN5-CITED2-PKA signaling modulep300/CBP-CITED2-TFAP2 ternary complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CITED2 transactivation domain (TAD) binds the CH1 domain of p300/CBP with high affinity and displaces the HIF-1α C-terminal TAD from a partially overlapping binding surface; a conserved LPEL motif in CITED2 is critical for this interaction, and mutation of LPEL abolishes p300 binding in vivo. High-resolution NMR solution structure of the CITED2 TAD–p300 CH1 complex was determined. NMR structure determination, in vitro binding assay, site-directed mutagenesis of LPEL motif, in vivo co-immunoprecipitation Nature structural biology High 12778114
2003 NMR structure of CBP TAZ1 bound to CITED2 activation domain reveals that CITED2 is intrinsically disordered and folds upon binding, forming an α-helix (αA) and extended structure that wraps around TAZ1. CITED2 and HIF-1α use partly overlapping but non-identical surfaces on TAZ1 (both contain an LP(E/Q)L motif binding the same TAZ1 junction) to compete for CBP, with CITED2 binding the αA/α1/α4 interface not used by HIF-1α. NMR structure determination, binding studies, structural comparison The Journal of biological chemistry High 14594809
2001 CITED2 physically interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2−/− embryonic fibroblasts and is rescued by ectopically expressed CITED2. Cited2−/− embryos die with cardiac malformations, adrenal agenesis, neural crest defects, and exencephaly. Co-immunoprecipitation, transient transfection reporter assay, Cited2 knockout mouse analysis Nature genetics High 11694877
2003 p300, TFAP2A, and endogenous CITED2 form a physical ternary complex in vivo; p300 co-activates TFAP2A only in the presence of CITED2, and this requires the histone acetyltransferase activity of p300. CITED2 interacts with the dimerization domain of TFAP2C/A. Full-length p300 and TFAP2A interact in mammalian two-hybrid assays only when CITED2 is co-transfected. Co-immunoprecipitation from transfected U2-OS cells, mammalian two-hybrid assay, HAT-deficient p300 mutant (D1399Y), transient transfection reporter assay The Journal of biological chemistry High 12586840
2002 CITED2 acts as a negative regulator of HIF-1α by competing for binding to CBP/p300. Loss of Cited2 leads to elevated HIF-1α-responsive gene expression (VEGF, Glut1, PGK1) in embryonic hearts and cultured fibroblasts under hypoxia, establishing Cited2 as an in vivo inhibitor of HIF-1 transcriptional activity. Cited2 knockout mouse, quantitative RT-PCR of HIF-1α target genes, hypoxia cell culture experiments Proceedings of the National Academy of Sciences of the United States of America High 12149478
2004 CITED2 and TFAP2 activate Pitx2c transcription at its promoter, and CITED2-null mice lack Nodal target gene expression (Pitx2c, Nodal, Ebaf) in the left lateral plate mesoderm, placing CITED2 upstream of a Nodal→Pitx2c pathway for left-right axis determination. CITED2 and TFAP2 were detected at the Pitx2c promoter by ChIP in embryonic hearts. Cited2 knockout mouse, in situ hybridization, chromatin immunoprecipitation (ChIP), transient transfection reporter assay Nature genetics High 15475956
2007 CITED2 interacts with WT1 to co-activate expression of SF-1 (Nr5a1) in the adrenogonadal primordium above the threshold required for adrenal development. Genetic and molecular evidence shows that Cited2 and Wt1 act in the same pathway to regulate Sf-1 dosage during adrenal cortex specification. Mouse genetics (Cited2/Wt1/Sf-1 compound mutants), gene expression analysis, genetic epistasis Development (Cambridge, England) High 17537799
2007 FOXO3a induces transcription of CITED2 during hypoxia in a HIF1-dependent manner. CITED2 then reduces HIF1 activity (negative feedback), limiting expression of proapoptotic HIF1 targets NIX and RTP801. FOXO3a inhibits HIF1-induced apoptosis via CITED2. Reporter assay, loss-of-function studies in fibroblasts and breast cancer cells, gene expression analysis Molecular cell High 18158893
2012 CITED2 inhibits acetylation of PGC-1α by blocking its interaction with the acetyltransferase GCN5, thereby enhancing PGC-1α transcriptional coactivation activity and increasing gluconeogenic gene expression. Insulin disrupts CITED2–GCN5 interaction via PI3K-Akt signaling. CITED2 abundance in liver is increased by glucagon-cAMP-PKA signaling during fasting. Co-immunoprecipitation, loss-of-function mouse model, reporter assay, gene expression analysis, pharmacological inhibition of PI3K-Akt Nature medicine High 22426420
2016 During fasting, PKA phosphorylates GCN5 in a CITED2-dependent manner, increasing GCN5 histone acetyltransferase (HAT) activity while attenuating PGC-1α acetylation. This substrate switch simultaneously promotes epigenetic activation of gluconeogenic gene promoters and PGC-1α-mediated coactivation, constituting a GCN5-CITED2-PKA signaling module. In vitro kinase assay, co-immunoprecipitation, HAT activity assay, mouse genetic models, gene expression analysis Nature communications High 27874008
2009 Conditional deletion of Cited2 in adult mice causes selective, cell-autonomous loss of hematopoietic stem cells (HSCs), leading to multilineage bone marrow failure. Concurrent deletion of Ink4a/Arf or Trp53 restores HSC functionality, placing CITED2 upstream of Ink4a/Arf and p53 in HSC maintenance. Conditional Cre-mediated knockout, bone marrow transplantation, genetic epistasis with Ink4a/Arf and Trp53 deletion Cell stem cell High 19951693
2006 CITED2 interacts physically with Smad2 and Smad3 (supported by co-IP, mammalian two-hybrid, and GST pulldown). p300 enhances CITED2-Smad3 interaction. CITED2 is recruited with Smad3 to the MMP9 promoter upon TGF-β stimulation and enhances TGF-β-mediated MMP9 upregulation and cell invasion. Co-immunoprecipitation, mammalian two-hybrid, GST pulldown, chromatin immunoprecipitation, luciferase reporter assay, invasion assay with siRNA knockdown Oncogene High 16619037
2007 Cited2 is a coactivator of HNF4α; physical interaction was demonstrated by co-IP. ChIP confirmed CITED2 is recruited to HNF4α-responsive promoters. Loss of Cited2 reduces HNF4α binding to target gene promoters in fetal liver, resulting in liver hypoplasia. Co-immunoprecipitation, chromatin immunoprecipitation, Cited2 knockout mouse liver analysis The EMBO journal High 17932483
2004 CITED2 was identified as a direct PPARα-interacting protein; it binds predominantly via the ligand-binding domain of PPARα and acts as a dose-dependent coactivator of PPARα-dependent transcriptional regulation in reporter assays, independently of ligand. cDNA library interaction cloning with bacterially expressed PPARα, co-immunoprecipitation, transient transfection reporter assay, stable overexpression/siRNA knockdown cell lines, microarray The Journal of biological chemistry Medium 15051727
2003 CITED2 overexpression in Cited2−/− fibroblasts induces Bmi1 and Mel18 (polycomb-group genes) and decreases Ink4a/ARF expression, rescuing premature proliferation arrest. Deletion of Ink4a/ARF rescues defective proliferation of Cited2−/− fibroblasts. Bmi1 and Mel18 retroviruses rescue proliferation, placing them downstream of CITED2. Retroviral complementation, Ink4a/ARF genetic deletion in Cited2−/− background, gene expression analysis Molecular and cellular biology High 14560011
2010 CITED2 competes with MMP transactivator Ets-1 for binding to p300, thereby suppressing MMP-1 expression. Moderate flow shear (5 dyn/cm²) induces CITED2 via a TGF-β-dependent pathway, dissociates Ets-1 from p300, and associates CITED2 with p300. CITED2 induction requires p38δ phosphorylation. Competitive binding assay, transcription reporter assay, co-immunoprecipitation, antisense/sense CITED2 transfection, p38δ pharmacological inhibition FASEB journal High 20826544
2003 CITED2 is induced by fluid shear stress and suppresses MMP-1 and MMP-13 expression in chondrocytes. Overexpression represses MMP-1/MMP-13, antisense CITED2 prevents shear-induced downregulation. CITED2 associates with p300, displacing Ets-1 from p300, in a TGF-β-dependent manner. Sense/antisense CITED2 transfection, co-immunoprecipitation, MMP activity assay, flow shear cell culture system The Journal of biological chemistry High 12960175
2010 CITED2 constitutively localizes in the nucleus and interacts with p300, preventing p65 from binding to p300, impairing p65 acetylation, and reducing p65 binding to NF-κB-responsive promoters. LPS induces CITED2 expression via NF-κB, establishing a negative feedback loop. CITED2 sensitizes cells to TNF-α-induced apoptosis. Co-immunoprecipitation, ChIP, reporter assay, siRNA knockdown, CITED2 overexpression, LPS stimulation of macrophages Journal of immunology High 21098220
2011 CITED2 inactivates HIF-1α N-terminal transactivation domain (NAD) activity by interfering with NAD binding to the CH1 domain of p300, while also blocking C-terminal TAD-p300 interaction; NAD interacts with both CH1 and CH3 domains of p300, but CITED2 only blocks CH1 binding. Co-immunoprecipitation, reporter assay for NAD- and CAD-dependent genes, domain mapping Biochimica et biophysica acta Medium 21925214
2007 CITED2 is degraded via the ubiquitin-proteasome pathway; proteasome inhibition (MG132) stabilizes CITED2 protein, which then inactivates HIF-1 by blocking HIF-1α-p300 interaction, explaining the paradoxical reduction of HIF-1 activity despite HIF-1α protein accumulation upon proteasome inhibition. Proteasome inhibitor MG132 treatment, CITED2 siRNA knockdown, reporter assay, Western blot Oncogene Medium 17906695
2015 FBXL5 directly interacts with CITED2 and promotes its proteasome-dependent degradation; FBXL5 depletion increases CITED2 protein levels, whereas FBXL5 overexpression decreases them. FBXL5-mediated CITED2 degradation impairs CITED2-CH1(p300) interaction and enables HIF-1α N-terminal TAD transcriptional activity. Co-immunoprecipitation, RNA interference, overexpression, reporter assay, mouse embryonic stem cells Archives of biochemistry and biophysics Medium 25956243
2012 CITED2 interacts with MYC and recruits p300 to promote MYC-p300-mediated transactivation of E2F3, driving G1/S cell cycle progression. CITED2 also interacts with HDAC1 and potentiates MYC-HDAC1 complex formation to suppress p21CIP1, inhibiting cellular quiescence. Co-immunoprecipitation, reporter assay, ChIP, siRNA knockdown, gain-of-function experiments Cell death and differentiation Medium 22814619
2012 HIF-1α deletion partially rescues impaired HSC quiescence and reconstitution capacity caused by Cited2 deficiency, and restores p57 and Hes1 (but not Egr1) expression, indicating that CITED2 regulates HSC quiescence via both HIF-1-dependent and HIF-1-independent pathways. Conditional double-knockout mouse (Cited2/HIF-1α), flow cytometry, bone marrow transplantation, gene expression profiling Blood High 22308296
2006 HIF-1α haploinsufficiency largely rescues outflow tract, interventricular septal, cardiac vascular, and hyposplenia defects in Cited2−/− embryos, and reduces HIF-1α-responsive gene mRNA levels in these hearts, providing in vivo evidence that CITED2 regulates cardiac development through inhibition of HIF-1 transcriptional activity. Cited2/HIF-1α compound mutant mouse, cardiac histology, MRI, gene expression analysis Developmental biology High 17022961
2012 CITED2 is recruited to the Oct4 promoter during early ESC differentiation to regulate Oct4 expression; loss of Cited2 delays silencing of pluripotency genes (Oct4, Klf4, Sox2, c-Myc) and impairs cardiomyocyte, hematopoietic, and neuronal differentiation. ChIP, gene knockout ESCs, qRT-PCR, differentiation assays The Journal of biological chemistry Medium 22761414
2015 Cited2 directly targets Nanog, Tbx3, and Klf4 in ESCs; acute loss of Cited2 reduces Nanog expression and ESC self-renewal, and this is rescued by constitutive Nanog expression. Cited2 is also required for efficient reprogramming of fibroblasts to iPSCs. Inducible Cre-mediated acute deletion, ChIP, rescue by Nanog overexpression, reprogramming assay Stem cells Medium 25377420
2009 CITED2 interacts with WT1 and SF1 to promote Sry expression in the XY gonad above the threshold required for testis determination; reducing Wt1 or Sf1 dosage in Cited2 mutants produces XY sex reversal, defining Sry as a downstream target of the CITED2/WT1/SF1 regulatory pathway. Compound mutant mouse genetics, gene expression analysis, genetic epistasis Human molecular genetics High 19457926
2012 CITED2 acts as a molecular chaperone guiding PRMT5 and p300 to nucleolin, thereby activating nucleolin and promoting epithelial-mesenchymal transition and prostate cancer metastasis. Co-immunoprecipitation, siRNA knockdown, xenograft mouse model, migration/invasion assay Nature communications Medium 30291252
2010 Loss of Cited2 from heart progenitors (using cardiac-specific Cre) does not alter development; heart defects in Cited2-null embryos arise from an extra-cardiac requirement for Cited2 in establishing the left-right body axis. Cited2 also acts as a potentiator of BMP signaling to counteract Nodal initiation in the left lateral plate mesoderm. Conditional cardiac-specific knockout, molecular genetic analysis, gene expression studies Human molecular genetics High 21224256
2008 Deletion of HIF-1α specifically in Cited2−/− lens eliminates excessive hyaloid vasculature hypercellularity without affecting the corneal-lenticular stalk phenotype; increased Pax6 dosage rescues the lens morphogenesis defect. This dissects two distinct CITED2 functions: one through HIF-1 in hyaloid vascular formation, and another upstream of or together with Pax6 in lens morphogenesis. Conditional double-knockout (lens-specific HIF-1α deletion in Cited2−/− background), Pax6 rescue genetics Development (Cambridge, England) High 18653562
2012 CITED2 is a direct effector of PPARγ; PPARγ binds the CITED2 promoter by ChIP, and PPARγ activation induces CITED2 expression in HCC cells. CITED2 knockdown increases cell viability and promotes G1-S transition; CITED2 overexpression suppresses HCC cell growth and upregulates CDK inhibitors p15, p21, p27. ChIP-PCR, adenovirus-PPARγ transduction, siRNA knockdown, gain-of-function proliferation assay Cancer Medium 23212831
2016 CITED2 is recruited to the IKKα promoter (by ChIP) and directly regulates IKKα expression; CITED2 knockdown reduces IKKα, inhibits both canonical and noncanonical NF-κB signaling, and impairs breast cancer cell invasion. IKKα re-expression in CITED2-knockdown cells rescues invasive ability. ChIP, siRNA knockdown, IKKα rescue experiment, NF-κB reporter assay, invasion assay, xenograft Molecular cancer research Medium 27216153
2011 CITED2 knockdown induces CBP/p300-mediated p53 acetylation at Lys373, reduces p53 ubiquitination, and stabilizes p53 protein, sensitizing cancer cells to cisplatin-induced apoptosis. shRNA knockdown, Western blot for p53 acetylation and ubiquitination, cisplatin sensitivity assay Journal of cellular physiology Medium 21660965
2008 CITED2 signals through PPARγ to promote neuronal death after DNA damage; CITED2 upregulation is downstream of Cdk4 but upstream of the mitochondrial apoptotic pathway and independent of p53. CITED2 overexpression promotes cortical neuron death; CITED2 deficiency protects. Gene array, retroviral overexpression, CITED2 knockout neurons, Cdk4 inhibition, camptothecin DNA damage model The Journal of neuroscience Medium 18495890
2012 Cited2 is required for maintenance of glycolytic metabolism in adult HSCs; Cited2 deficiency reduces Pdk2, Pdk4, LDHB, and LDHD expression, increases mitochondrial activity and ROS, and elevated Akt/mTORC1 signaling. PI3K-Akt inhibition (but not mTORC1 inhibition alone) partially rescues Pdk4 repression. Conditional Cited2 knockout, metabolic assays (glycolysis, mitochondrial activity, ROS, ATP), gene expression, pharmacological rescue with PI3K and mTOR inhibitors Stem cells and development Medium 24083546
2006 TGF-β downregulates Cited2 post-transcriptionally via the Smad pathway (Smad4-dependent, Smad7-inhibitable) by accelerating Cited2 mRNA turnover; this requires the C-terminal conserved region of the Cited2 coding sequence. Cited2 transcription is not affected by TGF-β. Nuclear run-on assay, Cited2 promoter reporter assay, Smad4 knockdown/Smad7 overexpression, mRNA stability assay with transcriptional inhibitors, deletion constructs The Journal of biological chemistry Medium 16675452
2016 CITED2 is recruited to the Vegfa promoter in mouse embryonic hearts (by ChIP) and cooperates with TFAP2 to stimulate VEGFA promoter activity. Cardiomyocyte-specific Cited2 knockout results in compact layer thinning, reduced capillary density, and reduced Vegfa expression. Cardiomyocyte-specific conditional knockout, ChIP, transient transfection reporter assay, MRI, vessel morphometry European heart journal High 22504313
2016 CITED2 is required for optimal PPARγ activation and anti-inflammatory gene expression in macrophages; CITED2 deficiency stabilizes HIF-1α protein, heightening proinflammatory gene expression. Overexpression of Egln3 or HIF-1α inhibition reverses elevated inflammation in Cited2-deficient macrophages. Myeloid-specific Cited2 KO mice are highly susceptible to endotoxin-induced sepsis. Myeloid-specific conditional knockout, gain- and loss-of-function, HIF-1α protein stability assay, Egln3 overexpression rescue, PPARγ reporter assay, LPS sepsis model Molecular and cellular biology High 29203644
2021 CITED2 deficiency in macrophages elevates IFNγ-induced STAT1 transcriptional activity, STAT1 enrichment on the IRF1 promoter, and IRF1-regulated pro-inflammatory gene expression. siRNA knockdown of IRF1 completely reverses elevated pro-inflammatory expression in CITED2-deficient macrophages. Myeloid CITED2-deficient mice on Apoe−/− background develop larger atherosclerotic lesions. Myeloid-specific conditional knockout, IRF1 siRNA rescue, ChIP for STAT1 at IRF1 promoter, atherosclerosis mouse model, transcriptomics/GSEA FASEB journal High 34365659
2013 Indoxyl sulfate (uremic toxin) markedly upregulates CITED2 via post-transcriptional mRNA stabilization involving the ERK1/2 pathway. Elevated CITED2 impairs HIF-1α C-terminal transactivation domain (CTAD) function without altering HIF-1α protein levels, thereby suppressing hypoxia-inducible gene expression. Reporter assay for HIF-1α CTAD activity, qRT-PCR, ERK1/2 inhibition, mRNA stability experiments, in vivo CKD models FASEB journal Medium 23792300
2016 CITED2 is recruited to the Cebpa promoter in embryonic lung (by ChIP) in cooperation with Tcfap2c to activate Cebpa transcription, which is required for alveolar epithelial cell differentiation and lung maturation. ChIP in E18.5 lungs, Cited2 knockout lung phenotype, gene expression analysis Developmental biology Medium 18358466
2014 In sinusoidal trophoblast giant cells and syncytiotrophoblasts, CITED2 non-cell-autonomously patterns pericytes associated with embryonic capillaries, likely via PDGF signaling. Loss of CITED2 in syncytiotrophoblasts causes subcellular mislocalization of the lactate transporter SLC16A3 (MCT4). Conditional trophoblast-specific Cre deletion, histology, immunofluorescence for MCT4 localization, PDGF signaling analysis Developmental biology Medium 24803182
2020 Computational structure-based modeling of TAZ1-CITED2-HIF-1α ternary system reveals that CITED2 forms the thermodynamically lowest energy complex with TAZ1 and binds TAZ1 faster kinetically than HIF-1α, explaining CITED2's superior competitive displacement of HIF-1α from p300. Structure-based computational modeling, free energy surface analysis, kinetic simulations Proceedings of the National Academy of Sciences of the United States of America Low 32123067
2021 A constrained (helix-stabilized) peptide derived from the CITED2 transactivation domain potently inhibits the HIF-1α–p300 interaction with high biochemical affinity, cell penetration, and serum stability, establishing that the CITED2-derived LPEL-containing helix is a pharmacologically tractable competitive inhibitor scaffold. In vitro binding affinity assay, cell penetration assay, serum stability assay, HIF-1α/p300 competition assay Journal of medicinal chemistry Medium 34472840

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nature genetics 282 11694877
2007 FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Molecular cell 235 18158893
2002 The essential role of Cited2, a negative regulator for HIF-1alpha, in heart development and neurulation. Proceedings of the National Academy of Sciences of the United States of America 178 12149478
2003 Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Nature structural biology 176 12778114
2004 Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. Nature genetics 175 15475956
1998 An endocrine-exocrine switch in the activity of the pancreatic homeodomain protein PDX1 through formation of a trimeric complex with PBX1b and MRG1 (MEIS2). Molecular and cellular biology 146 9710595
2002 Folic acid prevents exencephaly in Cited2 deficient mice. Human molecular genetics 132 11823447
2003 Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2. The Journal of biological chemistry 131 12586840
2005 Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development. Development (Cambridge, England) 114 15750185
2003 CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear. The Journal of biological chemistry 111 12960175
2007 Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. Development (Cambridge, England) 104 17537799
2005 Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Human mutation 104 16287139
2004 Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator. The Journal of biological chemistry 101 15051727
2003 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. The Journal of biological chemistry 97 14594809
2006 Loss of Cited2 affects trophoblast formation and vascularization of the mouse placenta. Developmental biology 93 16579983
2006 Cited2 modulates TGF-beta-mediated upregulation of MMP9. Oncogene 93 16619037
1998 MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity. Proceedings of the National Academy of Sciences of the United States of America 92 9811838
2009 Cited2 is an essential regulator of adult hematopoietic stem cells. Cell stem cell 91 19951693
2014 Regulation of arabidopsis flowering by the histone mark readers MRG1/2 via interaction with CONSTANS to modulate FT expression. PLoS genetics 84 25211338
2003 Transcriptional coactivator Cited2 induces Bmi1 and Mel18 and controls fibroblast proliferation via Ink4a/ARF. Molecular and cellular biology 77 14560011
2007 Cited1 and Cited2 are differentially expressed in the developing kidney but are not required for nephrogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 76 17615577
2010 Physiological loading of joints prevents cartilage degradation through CITED2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 74 20826544
2012 CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis. Nature medicine 66 22426420
2007 Cited2, a coactivator of HNF4alpha, is essential for liver development. The EMBO journal 66 17932483
2012 CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence. Cell death and differentiation 65 22814619
2008 Cited2 modulates hypoxia-inducible factor-dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc. Arthritis and rheumatism 63 19035510
2018 Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway. Nature communications 62 30291252
2010 Negative feedback regulation of NF-κB action by CITED2 in the nucleus. Journal of immunology (Baltimore, Md. : 1950) 62 21098220
2015 MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2. The Journal of biological chemistry 55 26240138
1997 MSG1 and its related protein MRG1 share a transcription activating domain. Gene 55 9434189
2012 HIF-1α deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency. Blood 53 22308296
2010 Loss of Cited2 causes congenital heart disease by perturbing left-right patterning of the body axis. Human molecular genetics 53 21224256
2006 Partial rescue of defects in Cited2-deficient embryos by HIF-1alpha heterozygosity. Developmental biology 50 17022961
2007 Cited2 is required for normal hematopoiesis in the murine fetal liver. Blood 49 17644732
2008 Cited2 is required for fetal lung maturation. Developmental biology 48 18358466
2007 A role for CITED2, a CBP/p300 interacting protein, in colon cancer cell invasion. FEBS letters 48 18054336
2008 Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis. Development (Cambridge, England) 47 18653562
1999 Molecular cloning and chromosomal localization of the human CITED2 gene encoding p35srj/Mrg1. Genomics 47 10552932
2009 The transcription co-factor CITED2 functions during sex determination and early gonad development. Human molecular genetics 46 19457926
2012 Pan-histone deacetylase inhibitor panobinostat sensitizes gastric cancer cells to anthracyclines via induction of CITED2. Gastroenterology 44 22465428
2014 Cited2 is required in trophoblasts for correct placental capillary patterning. Developmental biology 43 24803182
2013 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. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 23792300
2007 MRG-1, an autosome-associated protein, silences X-linked genes and protects germline immortality in Caenorhabditis elegans. Development (Cambridge, England) 42 17215300
2015 High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress. Diabetes 39 26450995
2014 CITED2 mutation and methylation in children with congenital heart disease. Journal of biomedical science 39 24456003
2018 CITED2 Restrains Proinflammatory Macrophage Activation and Response. Molecular and cellular biology 38 29203644
2011 Knockdown of CITED2 using short-hairpin RNA sensitizes cancer cells to cisplatin through stabilization of p53 and enhancement of p53-dependent apoptosis. Journal of cellular physiology 38 21660965
2010 Gonadal defects in Cited2-mutant mice indicate a role for SF1 in both testis and ovary differentiation. The International journal of developmental biology 37 19757380
2020 Diabetes-induced glucolipotoxicity impairs wound healing ability of adipose-derived stem cells-through the miR-1248/CITED2/HIF-1α pathway. Aging 36 32294623
2016 The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch. Nature communications 36 27874008
2009 CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer. British journal of cancer 35 19904269
2006 Post-transcriptional control of Cited2 by transforming growth factor beta. Regulation via Smads and Cited2 coding region. The Journal of biological chemistry 35 16675452
2020 Long Non-coding RNA FGD5-AS1 Regulates Cancer Cell Proliferation and Chemoresistance in Gastric Cancer Through miR-153-3p/CITED2 Axis. Frontiers in genetics 34 32849774
2010 Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left-right patterning defects. Human molecular genetics 34 20566713
2020 MRG1/2 histone methylation readers and HD2C histone deacetylase associate in repression of the florigen gene FT to set a proper flowering time in response to day-length changes. The New phytologist 33 32315442
2012 CITED2 is a novel direct effector of peroxisome proliferator-activated receptor γ in suppressing hepatocellular carcinoma cell growth. Cancer 33 23212831
2011 CITED2 controls the hypoxic signaling by snatching p300 from the two distinct activation domains of HIF-1α. Biochimica et biophysica acta 33 21925214
2008 Epiblastic Cited2 deficiency results in cardiac phenotypic heterogeneity and provides a mechanism for haploinsufficiency. Cardiovascular research 33 18440989
2018 The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells. The Journal of biological chemistry 32 29794136
2007 CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition. Oncogene 32 17906695
2007 Regulation of Cited2 expression provides a functional link between translational and transcriptional responses during hypoxia. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 31 17499866
2018 GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2. Cancer gene therapy 30 30177819
2002 MRG-1, a mortality factor-related chromodomain protein, is required maternally for primordial germ cells to initiate mitotic proliferation in C. elegans. Mechanisms of development 30 12175490
2016 Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 27307230
2014 CITED2-mediated human hematopoietic stem cell maintenance is critical for acute myeloid leukemia. Leukemia 28 25184385
2021 CircSNHG5 Sponges Mir-495-3p and Modulates CITED2 to Protect Cartilage Endplate From Degradation. Frontiers in cell and developmental biology 27 34277611
2021 CITED2 inhibits STAT1-IRF1 signaling and atherogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 34365659
2015 Proteasome regulation of the chromodomain protein MRG-1 controls the balance between proliferative fate and differentiation in the C. elegans germ line. Development (Cambridge, England) 27 25564623
2010 Identification of prospective factors promoting osteotropism in breast cancer: a potential role for CITED2. International journal of cancer 27 19642106
2015 FBXL5 modulates HIF-1α transcriptional activity by degradation of CITED2. Archives of biochemistry and biophysics 26 25956243
2023 CITED2 is a conserved regulator of the uterine-placental interface. Proceedings of the National Academy of Sciences of the United States of America 25 36626551
2012 Cited2 gene controls pluripotency and cardiomyocyte differentiation of murine embryonic stem cells through Oct4 gene. The Journal of biological chemistry 25 22761414
2020 CITED2 limits pathogenic inflammatory gene programs in myeloid cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 32697413
2020 CITED2 and the modulation of the hypoxic response in cancer. World journal of clinical oncology 24 32728529
2012 A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development. European heart journal 24 22504313
2011 The chromodomain protein MRG-1 facilitates SC-independent homologous pairing during meiosis in Caenorhabditis elegans. Developmental cell 24 22172672
2008 CITED2 signals through peroxisome proliferator-activated receptor-gamma to regulate death of cortical neurons after DNA damage. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 18495890
2007 CITED2 is expressed in human adrenocortical cells and regulated by basic fibroblast growth factor. The Journal of endocrinology 24 17283246
2019 CITED2 mediates the cross-talk between mechanical loading and IL-4 to promote chondroprotection. Annals of the New York Academy of Sciences 23 30891766
2017 Downregulation of CITED2 contributes to TGFβ-mediated senescence of tendon-derived stem cells. Cell and tissue research 23 28084522
2016 CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα. Molecular cancer research : MCR 23 27216153
2013 CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells. Biochemical and biophysical research communications 23 23811274
2000 MRG1 expression in fibroblasts is regulated by Sp1/Sp3 and an Ets transcription factor. The Journal of biological chemistry 23 11114295
2016 CITED2 Cooperates with ISL1 and Promotes Cardiac Differentiation of Mouse Embryonic Stem Cells. Stem cell reports 22 27818139
2015 Acute loss of Cited2 impairs Nanog expression and decreases self-renewal of mouse embryonic stem cells. Stem cells (Dayton, Ohio) 22 25377420
2012 CITED2 mutation links congenital heart defects to dysregulation of the cardiac gene VEGF and PITX2C expression. Biochemical and biophysical research communications 22 22735262
2016 Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells. Diabetes 21 27561725
2012 Functional significance of SRJ domain mutations in CITED2. PloS one 21 23082118
2008 Overexpression of the transcriptional coregulator Cited2 protects against glucocorticoid-induced atrophy of C2C12 myotubes. Biochemical and biophysical research communications 21 19032942
2006 Generation of conditional Cited2 null alleles. Genesis (New York, N.Y. : 2000) 21 17133411
2020 Investigations of the underlying mechanisms of HIF-1α and CITED2 binding to TAZ1. Proceedings of the National Academy of Sciences of the United States of America 20 32123067
2017 CITED2 affects leukemic cell survival by interfering with p53 activation. Cell death & disease 20 29072699
2016 Cited2 participates in cardiomyocyte apoptosis and maternal diabetes-induced congenital heart abnormality. Biochemical and biophysical research communications 20 27680315
2013 Cited2, a transcriptional modulator protein, regulates metabolism in murine embryonic stem cells. The Journal of biological chemistry 20 24265312
2000 Expression analysis of the chicken homologue of CITED2 during early stages of embryonic development. Mechanisms of development 20 11044621
2021 Potent Inhibition of HIF1α and p300 Interaction by a Constrained Peptide Derived from CITED2. Journal of medicinal chemistry 19 34472840
2020 The histone methylation readers MRG1/MRG2 and the histone chaperones NRP1/NRP2 associate in fine-tuning Arabidopsis flowering time. The Plant journal : for cell and molecular biology 19 32324922
2015 CITED2 silencing sensitizes cancer cells to cisplatin by inhibiting p53 trans-activation and chromatin relaxation on the ERCC1 DNA repair gene. Nucleic acids research 19 26384430
2009 Conditional deletion of Cited2 results in defective corneal epithelial morphogenesis and maintenance. Developmental biology 19 19632219
2013 Cited2 is required for the maintenance of glycolytic metabolism in adult hematopoietic stem cells. Stem cells and development 18 24083546