Affinage

RBPJ

Recombining binding protein suppressor of hairless · UniProt Q06330

Length
500 aa
Mass
55.6 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBPJ is the central nuclear transcription factor of the canonical Notch signaling pathway, functioning as a sequence-specific DNA-binding protein (consensus YRTGDGAD) that toggles between transcriptional repression and activation depending on cofactor occupancy (PMID:8622698, PMID:8065905). In the absence of Notch signaling, RBPJ recruits corepressor complexes containing SHARP, KDM5A, and KYOT2/RING1 to silence target genes by erasing H3K4 methylation marks; upon Notch activation, the Notch intracellular domain (NICD) displaces corepressors through high-affinity RAM domain binding and ankyrin repeat contacts with RBPJ N- and C-terminal regions, assembling a ternary activator complex with Mastermind (MAML) (PMID:30673607, PMID:20231316, PMID:11239004, PMID:9374409). Beyond canonical Notch signaling, RBPJ operates in Notch-independent contexts as a subunit of the PTF1 trimeric complex (with PTF1a) to specify pancreatic progenitors and GABAergic neurons, and as a repressor of HIF-driven angiogenic programs in cardiomyocytes (PMID:17938243, PMID:18198335, PMID:27357444). RBPJ activity is further modulated by nuclear export via RITA, proteasomal degradation through cyclin F-mediated ubiquitylation at Lys315, lysosomal degradation promoted by AICD, and competitive displacement of NICD/MAML by transcription factors YY1 and KLF4 (PMID:21102556, PMID:30254149, PMID:21558417, PMID:32075915, PMID:30607695).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Establishing RBPJ as a sequence-specific DNA-binding transcriptional repressor co-opted by viral (EBNA2) and cellular (Notch) activators resolved the fundamental question of how Notch signals reach the nucleus — RBPJ provides the DNA-tethering platform.

    Evidence In vitro binding, mutagenesis, EMSA, cotransfection reporter assays across multiple labs using EBV EBNA2 and Notch1 intracellular domain

    PMID:7853539 PMID:7957063 PMID:8065905 PMID:8622698

    Open questions at the time
    • Identity of the corepressor displaced by EBNA2/Notch was unknown
    • Structural basis of RBPJ-DNA interaction unresolved
    • Whether RBPJ acted as monomer in vivo was not confirmed
  2. 1995 High

    Demonstrating that RBPJ knockout causes embryonic lethality with somitogenesis and neural defects established RBPJ as essential for mammalian development, validating its non-redundant role downstream of Notch in vivo.

    Evidence Homologous recombination ES cell knockout mouse, phenotypic analysis before E10.5

    PMID:7588063

    Open questions at the time
    • Cell-type-specific contributions of RBPJ not dissected
    • Whether lethality was entirely Notch-dependent or included Notch-independent functions was unknown
  3. 1995 High

    Identification that RBPJ represses transcription through a corepressor mechanism — and that EBNA2 activates by both displacing this corepressor and supplying an activation domain — established the corepressor-switch model central to all subsequent Notch signaling studies.

    Evidence Cotransfection reporter assays with RBP-VP16 fusions and EBNA2 truncation mutants

    PMID:8559649

    Open questions at the time
    • Molecular identity of the corepressor remained unknown
    • How Notch NICD achieves the same switch was not yet mechanistically detailed
  4. 1997 High

    Dissecting the bipartite Notch-RBPJ interaction into a high-affinity RAM domain contact and a weaker ankyrin-repeat-mediated contact (mapped to RBPJ N- and C-terminal regions by 2001) explained how Notch assembles an activator on RBPJ and why both domains are needed for full transactivation.

    Evidence Transactivation assays in RBP-J-null OT11 cells with domain deletion mutants; chimeric RBP-J/RBP-L experiments

    PMID:11239004 PMID:9374409

    Open questions at the time
    • No atomic-resolution structure of RBPJ-NICD complex yet
    • Mastermind's role in the ternary complex not yet defined
  5. 2004 High

    Discovery that KyoT2 bridges RING1 (Polycomb) to RBPJ as a corepressor complex, and that KSHV RTA exploits RBPJ binding sites, revealed that multiple viral and cellular proteins converge on RBPJ as a regulatory hub.

    Evidence Yeast two-hybrid, GST pulldown, Co-IP, transactivation assays; EMSA and RBPJ-deficient cell assays for KSHV

    PMID:14999091 PMID:15194757

    Open questions at the time
    • Full repertoire of RBPJ corepressor complexes not catalogued
    • Structural basis of KyoT2-RBPJ interaction unknown
  6. 2007 High

    Demonstrating that RBPJ functions as a subunit of the PTF1 trimeric complex essential for early pancreatic development and later for GABAergic neuronal specification — independently of Notch — expanded RBPJ's role beyond canonical Notch signaling.

    Evidence Conditional KO mouse, PTF1a point mutant eliminating RBPJ binding, ChIP on Rbpjl promoter; Rbpj conditional KO in neural tube with Ptf1a knockin

    PMID:17938243 PMID:18198335

    Open questions at the time
    • How PTF1a-RBPJ complex excludes Notch coactivators mechanistically was not defined
    • Whether PTF1-J targets overlap with canonical Notch targets genome-wide was unexplored
  7. 2010 High

    Identification of KDM5A as a histone H3K4 demethylase component of the RBPJ repressor complex, and RITA as a nuclear-export factor for RBPJ, defined two new layers of regulation — chromatin modification and subcellular shuttling — that tune Notch output.

    Evidence Co-IP, ChIP showing H3K4me dynamics at RBPJ sites, Drosophila conservation (KDM5A); Co-IP, live imaging, Xenopus neurogenesis rescue (RITA)

    PMID:20231316 PMID:21102556

    Open questions at the time
    • Structural basis of KDM5A-RBPJ interaction unknown
    • Signals controlling RITA-mediated export not identified
    • Whether KDM5A and SHARP corepressor complexes are the same or parallel was unclear
  8. 2012 High

    Cell-type-specific RBPJ knockouts in myeloid and mesenchymal lineages showed that RBPJ controls osteoclastogenesis (via c-Fos/Blimp1/IRF-8 axis), macrophage polarization (via IRAK2-MNK1-eIF4E translational control of IRF8), and osteoblastogenesis (via Hey1-mediated NFATc1 repression), placing RBPJ at the center of skeletal and immune cell fate decisions.

    Evidence Myeloid- and mesenchyme-specific conditional KOs, signaling pathway dissection, ChIP, pharmacological rescue

    PMID:22249448 PMID:22457635 PMID:22610140

    Open questions at the time
    • Direct RBPJ binding sites at IRF8 translational regulators not mapped
    • Whether osteoclast and macrophage RBPJ functions are Notch-dependent vs. independent not fully separated
  9. 2013 High

    Genome-wide ChIP-Seq revealed that RBPJ chromatin occupancy is dynamic — increasing at NICD-co-occupied sites upon Notch activation — overturning the static-binding model and establishing that RBPJ exchanges between genomic sites in a Notch-dependent manner.

    Evidence ChIP-Seq for RBPJ, NICD, p300, histone marks in myogenic cells under Notch-active and -inhibited conditions

    PMID:23651858

    Open questions at the time
    • Mechanism driving RBPJ redistribution (e.g., cooperative binding, chromatin remodeling) not identified
    • Whether dynamic binding applies across all cell types was untested
  10. 2016 High

    Multiple studies expanded RBPJ's functional repertoire: in cardiomyocytes RBPJ represses HIF-driven angiogenesis independently of Notch; in Th17 cells RBPJ directly transactivates Il23r to sustain pathogenic identity; in BTICs RBPJ recruits CDK9/P-TEFb for transcriptional elongation; and RBPJ represses miR-182 to control osteoclastogenesis.

    Evidence Cardiomyocyte-specific KO and MI model; ChIP at Il23r and rescue with IL-23R overexpression; proteomic identification of RBPJ-CDK9 interaction; ChIP at miR-182 promoter with gain/loss-of-function

    PMID:27183593 PMID:27322055 PMID:27346359 PMID:27357444

    Open questions at the time
    • Whether CDK9 recruitment is a general RBPJ mechanism or BTIC-specific was unclear
    • Structural basis of RBPJ-HIF antagonism not defined
  11. 2017 High

    Crystal structures of RBPJ with RITA and with SHARP bound to DNA revealed that RITA mimics the Notch RAM domain for binding, while SHARP contacts a distinct surface essential for repression — providing the first atomic-level understanding of how corepressors and competitors engage RBPJ.

    Evidence X-ray crystallography, ITC, structure-based mutagenesis with cellular reporter assays

    PMID:28487372 PMID:30673607

    Open questions at the time
    • No full ternary RBPJ-NICD-MAML structure available
    • How SHARP and KDM5A corepressors are coordinated structurally is unknown
  12. 2018 High

    Cyclin F (SCF complex) ubiquitylates RBPJ at Lys315 for proteasomal degradation under metabolic stress, while AICD promotes RBPJ lysosomal degradation — establishing that RBPJ protein levels are actively controlled by two distinct degradation pathways.

    Evidence Ubiquitylation assays with Lys315 mutagenesis, proteasome/lysosome inhibitors, Co-IP of AICD/Fbw7/NICD trimeric complex, in vivo tumor models

    PMID:21558417 PMID:30254149

    Open questions at the time
    • Physiological signals triggering cyclin F-RBPJ ubiquitylation beyond metabolic stress not defined
    • Whether these degradation pathways operate in all tissues is unknown
  13. 2019 High

    YY1 and KLF4 were identified as competitive inhibitors that displace NICD/MAML from RBPJ at specific genomic loci, revealing that transcription factor competition at the RBPJ complex surface fine-tunes Notch output in endothelial cells and angiogenesis.

    Evidence Co-IP, domain mapping, MAML1 competition assays, endothelial-specific KO, ChIP at DLL4 intron 3

    PMID:30607695 PMID:32075915

    Open questions at the time
    • Whether other transcription factors similarly compete for RBPJ is unknown
    • Structural details of YY1-RBPJ and KLF4-RBPJ interfaces lacking
  14. 2019 High

    Multi-omic analyses in mature T-cells and ESCs demonstrated that RBPJ functions as a Notch-independent repressor genome-wide, silencing Notch target genes in the absence of active signaling and contributing to exit from naive pluripotency alongside Etv5 and Tcf3.

    Evidence RNA-Seq, ChIP-Seq, ATAC-Seq in T-cells; triple conditional KO (Etv5/Rbpj/Tcf3) in ESCs

    PMID:31031137 PMID:35848919

    Open questions at the time
    • Genome-wide identification of Notch-independent RBPJ corepressor complexes incomplete
    • Whether RBPJ repressor function in pluripotency uses the same corepressors (SHARP, KDM5A) as in Notch-off T-cells is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the full structural model of ternary RBPJ-NICD-MAML on DNA, the complete inventory of Notch-independent RBPJ complexes and their target gene networks, and how RBPJ protein turnover is coordinated across tissues and signaling states.
  • No full ternary RBPJ-NICD-MAML crystal or cryo-EM structure
  • Genome-wide catalog of Notch-independent RBPJ binding partners incomplete
  • Tissue-specific regulation of RBPJ degradation pathways not systematically characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-74160 Gene expression (Transcription) 8 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 4
Partners
CDK9KDM5AMAML1NOTCH1PTF1ARITA1SHARPYY1
Complex memberships
PTF1 trimeric complex (PTF1a/E-protein/RBPJ)RBPJ-NICD-MAML ternary activator complexRBPJ-SHARP corepressor complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 RBP-J kappa (CBF1) is a sequence-specific DNA-binding transcriptional repressor that is recruited by EBV EBNA2 to its responsive elements; EBNA2 physically interacts with RBP-J kappa to transactivate gene expression via CBF1 tethering to DNA, partly by abolishing CBF1-mediated repression. The same mechanism is used by activated Notch1 intracellular domain (NotchIC), which binds to the transcriptional repression domain of CBF1 (aa179-361) through its N-terminal 114-amino-acid region (not the ankyrin repeats). In vitro binding assay, cotransfection two-hybrid assay, immunoprecipitation Molecular and cellular biology High 8622698
1994 RBP-J kappa (KBF2) binds DNA as a monomer; site-directed mutagenesis identified the region encompassing residues 218Arg–227Arg as critical for DNA-binding activity, while the integrase motif (230His–269His) is not required for DNA binding. Site-directed mutagenesis, in vitro DNA-binding assay with mutant proteins expressed in COS cells Nucleic acids research High 8065905
1994 RBP-J kappa directly interacts with EBV EBNA2 through EBNA2 conserved region CR6 (residues ~318–327, containing WW323,324); mutation of CR6 hydrophobic residues severely impairs RBP-J kappa binding and EBNA2 transactivation, establishing CR6 as the crucial interface. EMSA competition assay, deletion/point mutant cotransfection, synthetic peptide competition Journal of virology High 7853539
1994 EBV EBNA2 interacts with RBP-J kappa (purified to homogeneity from Raji cells) through the EBNA2-responsive element of the TP1 promoter; purified RBP-J kappa and in vitro-translated RBP-J both bind EBNA2 and the EBNA-2RE, establishing RBP-J kappa as the cellular anchor for EBNA2 transcriptional activation. EMSA competition, affinity purification, SDS-PAGE silver staining, anti-RBP-J monoclonal antibody confirmation, in vitro translation The EMBO journal High 7957063
1994 Drosophila Hairless inhibits the DNA-binding activity of both Su(H) (Drosophila RBPJ ortholog) and human RBP-J kappa through direct protein-protein interaction, identifying a mechanism for negative regulation of RBP-J transcriptional activity. Transcriptional activation driven by Su(H) in transfected S2 cells is inhibited by Hairless. In vitro pulldown, EMSA, transfection assay in Drosophila S2 cells Genes & development High 7958912
1995 RBP-J kappa functions as a transcriptional repressor via a co-repressor; this repression can be counteracted by EBNA2 (which provides an activation domain and interferes with co-repressor function), revealing that EBNA2 activates transcription both by displacing a co-repressor from RBP-J kappa and by supplying an activation domain. Cotransfection reporter assay with RBP-VP16 fusion and EBNA2 truncation mutants Nucleic acids research High 8559649
1995 Homologous deletion of RBP-J kappa in mice causes embryonic lethality before E10.5 with defects in somitogenesis, body axis turning, microencephaly, and placental development; somites fail to express myogenin despite expressing Mox1, demonstrating an essential role for RBP-J kappa in postimplantation mouse development. Homologous recombination in ES cells, knockout mouse analysis Development (Cambridge, England) High 7588063
1996 EBNA3A, EBNA3B, and EBNA3C all interact with RBP-J kappa through their N-terminal regions (EBNA3A aa1–138, EBNA3B aa1–311, EBNA3C aa1–183); EBNA3A and EBNA3B can inhibit RBP-J kappa DNA binding in vitro, linking the EBNA3 gene family to differential regulation of RBP-J kappa-dependent promoters. GST pulldown, co-immunoprecipitation, EMSA inhibition assay Journal of virology High 8627785
1996 C. elegans LAG-1, the ortholog of RBP-J/CBF1, binds specifically to the DNA sequence RTGGGAA (the CBF1/Su(H) binding site) and acts as a transcriptional regulator linking the LIN-12/GLP-1 (Notch) receptors to downstream target genes. DNA binding assay with purified LAG-1, genetic analysis in C. elegans Development (Cambridge, England) High 8625826
1997 The Notch1 intracellular region (RAMIC) activates transcription through RBP-J via two separable domains: the RAM domain (high-affinity RBP-J binding) and the IC/ankyrin domain (weaker RBP-J interaction but transactivation-competent). RAM domain synergistically enhances IC-mediated transactivation, proposed to compete with a putative co-repressor for binding to RBP-J. Transactivation activity requires RBP-J (demonstrated in RBP-J-null OT11 cells), and is coupled to suppression of myogenic differentiation. Transactivation assays in RBP-J-null cell line (OT11), deletion mutant analysis, myogenesis assay with C2C12 cells Development (Cambridge, England) High 9374409
1995 Su(H) (Drosophila ortholog of RBP-J) binds to the TGTGGGAA sequence in the E(spl)m8 promoter and transactivates E(spl)m8 both in cultured Drosophila cells and in vivo, placing Su(H)/RBP-J directly upstream of E(spl) in the neurogenic gene cascade downstream of Notch. DNA binding assay, transfection reporter assay, in vivo transactivation Idengaku zasshi Medium 7546844
2001 The N- and C-terminal regions of RBP-J interact with the ankyrin repeats of the Notch1 intracellular domain (RAMIC); in vitro binding assays and transcriptional assays in RBP-J-null cells show that mutations in these RBP-J terminal regions abolish ankyrin-repeat-dependent transactivation without affecting DNA binding or RAM domain binding. Chimeric experiments with RBP-L confirm these regions confer RAMIC-induced transactivation. In vitro binding assay, transactivation assay in RBP-J-null OT11 cells, chimeric RBP-J/RBP-L proteins Nucleic acids research High 11239004
2004 RING1 (polycomb group protein) inhibits Notch-induced transactivation through RBP-J indirectly by forming a three-molecule complex with KyoT2 (LIM domain protein) and RBP-J: KyoT2 binds both RBP-J (via its RBP-J-binding motif) and RING1 (via its LIM domains), recruiting RING1 to suppress RBP-J-mediated transcription. RING1 does not directly interact with RBP-J. Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, transactivation assay Nucleic acids research High 14999091
2004 RBP-J (CSL) is essential for KSHV RTA-mediated activation of the K14/vGPCR promoter: RBP-J binds RTA and recruits it to RBP-J cognate recognition sites (including a novel variant site A and canonical site C), and RBP-J-deficient cells show dramatic loss of K14/vGPCR promoter function. EMSA, deletion/scanning mutagenesis of promoter, RBP-J-deficient cell functional assay Journal of virology High 15194757
2007 RBPJ functions within the trimeric PTF1 transcription factor complex (with PTF1a bHLH and an E-protein) during early pancreatic development; the PTF1a–RBPJ interaction (not the PTF1a–RBPJL interaction) is essential for early pancreatic growth, morphogenesis, and lineage fate decisions. A single amino acid change in PTF1a that eliminates RBPJ binding (but not RBPJL binding) phenocopies Ptf1a-null pancreatic defects. Later, RBPJ is replaced by RBPJL in the PTF1 complex to drive acinar differentiation, and the Rbpjl gene is a direct PTF1 target with PTF1-J binding its promoter. Conditional knockout mouse, targeted PTF1a point mutant, ChIP on Rbpjl promoter Genes & development High 17938243
2008 Ptf1a and Rbpj form a complex (PTF1-J) required in vivo for specification of GABAergic inhibitory neurons in the dorsal spinal cord; a Ptf1a mutant unable to bind Rbpj cannot induce GABAergic (Pax2+) fate or suppress glutamatergic (Tlx3+) fate. This Rbpj function is independent of canonical Notch signaling, as shown by Rbpj conditional knockout which causes loss of GABAergic specification. Conditional knockout mouse (Rbpj), Ptf1a point mutant knockin, in ovo electroporation (chick), mouse neural tube analysis Genes & development High 18198335
2009 Neurog2 is a direct transcriptional target of the PTF1-J (Ptf1a-Rbpj) complex: a Neurog2 dorsal neural tube enhancer requires a PTF1-J binding site for activity; Ptf1a gain/loss of function modulates this enhancer; ChIP from neural tube tissue shows Ptf1a binding to the Neurog2 enhancer. Enhancer reporter assay (mouse/chick), in vivo ChIP from neural tube, gain/loss-of-function with Ptf1a Development (Cambridge, England) High 19641016
2010 KDM5A (histone demethylase) is an integral component of the RBP-J repressor complex: KDM5A physically interacts with RBP-J; histone H3K4 methylation is dynamically erased and re-established at RBP-J binding sites upon inhibition and reactivation of Notch signaling. This interaction is conserved in Drosophila and is required for Notch-induced growth and tumorigenesis responses. Co-immunoprecipitation (physical interaction), ChIP (H3K4me dynamics at RBP-J sites), Drosophila genetic conservation studies Genes & development High 20231316
2010 RITA (RBP-J interacting and tubulin associated; C12ORF52) is a novel RBP-J/CBF1-interacting protein that binds tubulin in the cytoplasm and shuttles between cytoplasm and nucleus; RITA exports RBP-J from the nucleus, thereby downregulating Notch-mediated transcription. RITA reverses Notch-induced loss of primary neurogenesis in Xenopus. Protein interaction assay (Co-IP), subcellular localization (live imaging/shuttling), Xenopus neurogenesis functional assay, transcriptional reporter assay The EMBO journal High 21102556
2010 Osteosclerosis caused by Notch1 intracellular domain (NICD) expression in osteoblasts is completely rescued by selective deletion of Rbpj in osteoblasts, demonstrating that NICD-driven osteosclerosis is entirely Rbpj-dependent (canonical). Rbpj-dependent molecular changes (proliferation induction, differentiation block) are fully reversed by Rbpj deletion. Conditional KO epistasis (Rbpj deletion on Notch GOF background), cellular and molecular bone analysis Journal of bone and mineral research High 20499347
2011 Wt1a, Foxc1a, and Rbpj physically interact with each other in zebrafish (GST pulldown and Co-IP); only Rbpj binds the Notch intracellular domain (NICD). In transactivation assays, combinations of Wt1, FoxC1/2, and NICD synergistically induce the Hey1 promoter, and rbpj morphants develop fewer podocytes. GST pulldown, co-immunoprecipitation, transactivation assay, morpholino knockdown in zebrafish Developmental biology High 21871448
2012 RBP-J suppresses TNF-induced osteoclastogenesis by attenuating c-Fos activation and suppressing B lymphocyte-induced maturation protein-1 (Blimp1) induction, thereby preventing downregulation of transcriptional repressors (IRF-8) that block osteoclast differentiation. Mechanistically, RBP-J blocks induction of NFATc1 (master osteoclast regulator) in a RANK-independent manner, and RBP-J activation in osteoclast precursors suppresses arthritic bone resorption. Myeloid-specific conditional KO, RANK-deficient mouse reconstitution, RBP-J activation in precursors, molecular target analysis The Journal of experimental medicine High 22249448
2012 Notch-RBP-J signaling controls IRF8 protein synthesis in macrophages by selectively augmenting IRAK2-dependent TLR4 signaling to kinase MNK1 and downstream translational control through eIF4E; IRF8 in turn induces downstream M1 macrophage-associated genes. Conditional KO (myeloid RBP-J deletion), signaling pathway analysis, IRF8 protein synthesis assay Nature immunology High 22610140
2012 Notch-RBPjk signaling suppresses osteoblastogenesis in part through Hey1-mediated inhibition of NFATc1: RBPjk deletion in mesenchymal progenitors increases NFATc1 expression in bone; Hey1 binds to and suppresses the NFATc1 promoter; pharmacological NFAT inhibition alleviates the high-bone-mass phenotype of RBPjk-deleted mice. Conditional KO (RBPjk in mesenchyme), Hey1/HeyL double KO, ChIP (Hey1 at NFATc1 promoter), pharmacological rescue PLoS genetics High 22457635
2013 RBPJ exhibits dynamic (not static) chromatin binding: at sites co-occupied by NICD, RBPJ binding increases upon Notch activation; at a distinct set of sites (lacking NICD/p300), RBPJ binds DNA statically regardless of Notch activity. This was determined by genome-wide RBPJ ChIP-Seq combined with NICD, p300, and histone modification profiling in myogenic cells. ChIP-Seq (RBPJ, NICD, p300, H3K4me3, H3K4me1, H3K27ac) under active vs. inhibitory Notch conditions Genes & development High 23651858
2013 The Rbpj/NICD transcription complex is recruited to RBP-J binding sites upstream of the Sox9 promoter (shown by ChIP) and is associated with transcriptional repression of Sox9 in chondrocytes; Rbpj deletion in Notch GOF background restores Sox9 protein levels, demonstrating Rbpj-dependent suppression of Sox9 during chondrogenesis. Conditional Rbpj KO on Notch GOF background (genetic epistasis), ChIP (Rbpj/NICD at Sox9 promoter), molecular analysis Journal of bone and mineral research High 22991339
2016 RBPJ directly binds and transactivates the Il23r promoter in Th17 cells, driving IL-23R expression; RBPJ also represses IL-10 production in Th17 cells. Absence of RBPJ prevents IL-23R upregulation, reduces Th17 stability, and blocks autoimmune tissue inflammation; overexpression of IL-23R rescues the defect in RBPJ-deficient Th17 cells. Conditional KO, ChIP (RBPJ at Il23r promoter), reporter assay, IL-23R overexpression rescue Cell reports High 27346359
2016 RBPJ maintains brain tumor-initiating cells (BTICs) by binding CDK9 (a component of P-TEFb) at target gene promoters to enhance transcriptional elongation; this is distinct from canonical Notch target gene regulation. MYC binds the RBPJ promoter to drive RBPJ expression in BTICs; BET bromodomain inhibition decreases MYC and RBPJ. Proteomic analysis (RBPJ-CDK9 interaction), ChIP, BET inhibitor treatment, RBPJ knockdown, BTIC self-renewal assay The Journal of clinical investigation High 27322055
2016 RBPJ controls expression of miR-182, which promotes TNF-induced osteoclastogenesis; RBP-J represses miR-182 by binding to open chromatin regions in the miR-182 promoter (ChIP). miR-182 targets Foxo3 and Maml1 (inhibitors of osteoclastogenesis) and positively regulates NFATc1 and Blimp1. High-throughput miRNA sequencing, ChIP (RBPJ at miR-182 promoter), gain/loss-of-function of miR-182, target validation Journal of immunology High 27183593
2016 RBPJ controls angiogenesis in cardiomyocytes independently of Notch by antagonizing hypoxia-inducible factor (HIF) activity on pro-angiogenic and angiostatic factor genes; cardiomyocyte-specific Rbpj deletion increases microvascularization and improves heart function after myocardial infarction. Cardiomyocyte-specific conditional KO, gene expression analysis, myocardial infarction model Nature communications High 27357444
2017 X-ray crystal structure of the RBP-J·RITA complex bound to DNA was determined; RITA binds RBP-J similarly to the RAM domain of Notch (at the same region), while biochemical and cellular assays show RITA also interacts with additional RBP-J regions. Structure-based mutants that disrupt the RITA-RBP-J interaction confirm their roles in Notch target gene repression. X-ray crystallography, isothermal titration calorimetry (ITC), structure-based mutagenesis, Co-IP, transcriptional reporter assay The Journal of biological chemistry High 28487372
2018 Cyclin F (SCF E3 ubiquitin ligase substrate recognition subunit) mediates polyubiquitylation of RBPJ at Lys315 under metabolic stress conditions (in a FOXO1-dependent manner), leading to proteasomal degradation of RBPJ. Additionally, AICD promotes degradation of RBP-Jk through the lysosomal pathway, preferentially targeting non-phosphorylated RBP-Jk. Ubiquitylation assay, site-directed mutagenesis (Lys315), proteasome inhibitor experiments, co-IP, cyclin F overexpression/KO, mouse tumor models Cancer research High 30254149
2011 APP intracellular domain (AICD) attenuates Notch1 signaling by promoting degradation of Notch1-IC (via Fbw7-dependent proteasomal pathway, forming a Notch1-IC/Fbw7/AICD trimeric complex) and of RBP-Jk (via lysosomal pathway), dissociating the Notch1-IC–RBP-Jk complex. Co-immunoprecipitation (trimeric complex), proteasome/lysosome inhibitor experiments, overexpression and knockdown, transcriptional reporter assay Journal of cell science High 21558417
2019 Crystal structure of RBPJ bound to the corepressor SHARP and DNA reveals the mode of SHARP binding to RBPJ; RBPJ mutants deficient for SHARP binding are incapable of repressing Notch-responsive gene transcription in cells, demonstrating that SHARP interaction is required for RBPJ repressor function. X-ray crystallography, biophysical assays, structure-based mutagenesis, transcriptional repression assay in cells Cell reports High 30673607
2019 RIN1 (RBPJ Inhibitor-1), a small molecule, disrupts both the NOTCH-RBPJ interaction and the RBPJ-SHARP corepressor interaction; RIN1 induces gene expression changes resembling RBPJ siRNA silencing (rather than Notch-level inhibition), inhibits hematologic cancer cell proliferation, and promotes skeletal muscle differentiation from C2C12 myoblasts. Small molecule screen, gene expression profiling, co-immunoprecipitation disruption assay, cell proliferation assay, myoblast differentiation assay Scientific reports High 31346210
2019 RBPJ functions as an independent repressor (Notch-independent) in mature T-cells lacking active Notch signaling; RBPJ depletion upregulates many Notch target genes. ChIP-Seq and ATAC-Seq define four gene clusters differentially regulated by RBPJ and/or Notch, including early (Hes1, Hey1) and late Notch-responsive genes (IL2ra). Squelching of corepressor KYOT2/FHL1 also derepresses Notch target genes. RNA-Seq, ChIP-Seq (RBPJ), ATAC-Seq, NICD1 ectopic expression, KYOT2 squelching in mature T-cells Nucleic acids research High 35848919
2019 In formative pluripotency transition, RBPJ upregulation (independent of Notch) prevents re-expression of naive factors TBX3 and NANOG; triple deletion of Etv5, Rbpj, and Tcf3 locks ESCs in self-renewal even under differentiation stimuli, demonstrating complementary roles of RBPJ in exiting the naive state. Triple conditional KO (Etv5, Rbpj, Tcf3), ESC differentiation assay, genome relocation analysis Cell stem cell High 31031137
2019 Endothelial YY1 directly binds to the N-terminal domain of RBPJ and competes with Notch coactivator MAML1 for binding to RBPJ, thereby impairing NICD/MAML1/RBPJ complex formation and repressing Notch-dependent gene expression; endothelial YY1 deletion impairs sprouting angiogenesis and leads to embryonic lethality. Co-immunoprecipitation (YY1-RBPJ interaction), domain mapping, competition assay with MAML1, EC-specific KO mouse, retinal angiogenesis analysis Proceedings of the National Academy of Sciences of the United States of America High 32075915
2016 KLF4 disables the activity of the Notch transcriptional activator RBP-J by interfering with binding of co-activators NICD and MAML at intron 3 of the Notch ligand DLL4, thereby inhibiting DLL4 expression and promoting endothelial tip cell behavior during retinal vascular development. Transgenic overexpression, ChIP (KLF4, RBP-J, NICD, MAML at DLL4 intron 3), retinal angiogenesis analysis, oxygen-induced retinopathy model Angiogenesis High 30607695
1995 Anti-RBP-Jkappa monoclonal antibodies stain nuclei of undifferentiated embryonic stem and F9 cells but not differentiated cell lines; upon retinoic acid-induced differentiation of F9 cells, free nuclear RBP-Jkappa disappears, while chromatin-bound RBP-Jkappa (detected by biochemical fractionation) remains, suggesting that chromatin binding masks antibody epitopes and implicating RBP-J kappa in pluripotent cell identity. Immunostaining with anti-RBP-J monoclonal antibodies, biochemical subcellular fractionation, retinoic acid-induced differentiation Journal of biochemistry Medium 8690727
2010 RBP-J mediates Jagged1 autoamplification of Notch signaling in macrophages: TLR-induced Jagged1 expression is strongly dependent on RBP-J, as well as Notch1/2 receptors and γ-secretase, demonstrating that Jagged1 is an RBP-J target gene activated by early TLR-Notch cooperation to create a feed-forward loop. Conditional KO macrophages (RBP-J deficient), Jagged1 expression analysis, inhibitor studies (γ-secretase, Notch1/2 siRNA) Journal of immunology High 20870935

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. The Journal of experimental medicine 716 17591855
1995 Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development (Cambridge, England) 423 7588063
2002 Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nature immunology 397 11967543
1996 Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Molecular and cellular biology 393 8622698
2012 Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nature immunology 362 22610140
1997 Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development (Cambridge, England) 261 9374409
2013 Dynamic binding of RBPJ is determined by Notch signaling status. Genes & development 210 23651858
2011 Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. Proceedings of the National Academy of Sciences of the United States of America 208 21737748
1996 lag-1, a gene required for lin-12 and glp-1 signaling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H). Development (Cambridge, England) 193 8625826
1994 Epstein-Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP-J kappa, the homologue of Drosophila Suppressor of Hairless. The EMBO journal 190 7957063
1996 The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes to cells : devoted to molecular & cellular mechanisms 177 9078362
1994 Inhibition of the DNA-binding activity of Drosophila suppressor of hairless and of its human homolog, KBF2/RBP-J kappa, by direct protein-protein interaction with Drosophila hairless. Genes & development 162 7958912
2010 Histone demethylase KDM5A is an integral part of the core Notch-RBP-J repressor complex. Genes & development 150 20231316
2012 TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. The Journal of experimental medicine 149 22249448
1996 The amino-terminal domains of Epstein-Barr virus nuclear proteins 3A, 3B, and 3C interact with RBPJ(kappa). Journal of virology 142 8627785
2012 Genome-wide analysis of N1ICD/RBPJ targets in vivo reveals direct transcriptional regulation of Wnt, SHH, and hippo pathway effectors by Notch1. Stem cells (Dayton, Ohio) 133 22232070
2005 Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas. Journal of molecular medicine (Berlin, Germany) 132 16283144
2007 Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. Genes & development 127 17938243
2003 Notch/RBP-J signaling regulates epidermis/hair fate determination of hair follicular stem cells. Current biology : CB 111 12593800
2008 A nonclassical bHLH Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling. Genes & development 109 18198335
2000 Notch signalling via RBP-J promotes myeloid differentiation. The EMBO journal 108 10835354
2010 Autoamplification of Notch signaling in macrophages by TLR-induced and RBP-J-dependent induction of Jagged1. Journal of immunology (Baltimore, Md. : 1950) 106 20870935
2016 RBPJ Controls Development of Pathogenic Th17 Cells by Regulating IL-23 Receptor Expression. Cell reports 98 27346359
2005 Notch-mediated CBF-1/RBP-J{kappa}-dependent regulation of human vascular smooth muscle cell phenotype in vitro. American journal of physiology. Cell physiology 96 15987768
2004 CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. Experimental cell research 89 15350543
2009 Rbpj cell autonomous regulation of retinal ganglion cell and cone photoreceptor fates in the mouse retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 86 19828801
2019 Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency. Cell stem cell 82 31031137
2012 Physiological notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1. PLoS genetics 80 22457635
2010 Replacement of Rbpj with Rbpjl in the PTF1 complex controls the final maturation of pancreatic acinar cells. Gastroenterology 79 20398665
2011 Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL. Arteriosclerosis, thrombosis, and vascular biology 74 21493891
1995 RBP-J kappa repression activity is mediated by a co-repressor and antagonized by the Epstein-Barr virus transcription factor EBNA2. Nucleic acids research 74 8559649
1994 Site-directed mutagenesis study on DNA binding regions of the mouse homologue of Suppressor of Hairless, RBP-J kappa. Nucleic acids research 74 8065905
2019 RBPJ-dependent Notch signaling initiates the T cell program in a subset of thymus-seeding progenitors. Nature immunology 72 31636466
2011 Wt1a, Foxc1a, and the Notch mediator Rbpj physically interact and regulate the formation of podocytes in zebrafish. Developmental biology 72 21871448
1995 Contribution of conserved amino acids in mediating the interaction between EBNA2 and CBF1/RBPJk. Journal of virology 71 7853539
2004 RBP-J (CSL) is essential for activation of the K14/vGPCR promoter of Kaposi's sarcoma-associated herpesvirus by the lytic switch protein RTA. Journal of virology 65 15194757
2010 Two opposing roles of RBP-J in Notch signaling. Current topics in developmental biology 64 20816397
2008 Melanoblasts' proper location and timed differentiation depend on Notch/RBP-J signaling in postnatal hair follicles. The Journal of investigative dermatology 64 18463680
2022 Exosomal hsa_circ_0004658 derived from RBPJ overexpressed-macrophages inhibits hepatocellular carcinoma progression via miR-499b-5p/JAM3. Cell death & disease 61 35013102
2010 Osteosclerosis owing to Notch gain of function is solely Rbpj-dependent. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 61 20499347
2019 Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes. Nature communications 60 31249304
2016 RBP-J-Regulated miR-182 Promotes TNF-α-Induced Osteoclastogenesis. Journal of immunology (Baltimore, Md. : 1950) 60 27183593
2011 Transcriptional regulator RBP-J regulates the number and plasticity of renin cells. Physiological genomics 60 21750232
2013 Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 59 22991339
1993 Human Jk recombination signal binding protein gene (IGKJRB): comparison with its mouse homologue. Genomics 58 8406481
2016 RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. The Journal of clinical investigation 57 27322055
2010 RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J. The EMBO journal 57 21102556
2004 RING1 inhibits transactivation of RBP-J by Notch through interaction with LIM protein KyoT2. Nucleic acids research 55 14999091
2021 Sox9 and Rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors. Nature communications 53 33963183
2014 Loss of the Notch effector RBPJ promotes tumorigenesis. The Journal of experimental medicine 52 25512468
2019 Rbpj expression in regulatory T cells is critical for restraining TH2 responses. Nature communications 51 30962454
2016 Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis. Cardiovascular research 50 27496872
2014 RBPJ in mouse Sertoli cells is required for proper regulation of the testis stem cell niche. Development (Cambridge, England) 50 25406395
1995 Suppressor of hairless, the Drosophila homologue of RBP-J kappa, transactivates the neurogenic gene E(spl)m8. Idengaku zasshi 50 7546844
2001 The N- and C-terminal regions of RBP-J interact with the ankyrin repeats of Notch1 RAMIC to activate transcription. Nucleic acids research 49 11239004
2019 Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ. Scientific reports 48 31346210
2014 Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice. Development (Cambridge, England) 48 25209249
2009 Neurog2 is a direct downstream target of the Ptf1a-Rbpj transcription complex in dorsal spinal cord. Development (Cambridge, England) 48 19641016
2008 Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms. Molecular and cellular biochemistry 46 18777163
2008 Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis. Oncogene 44 18836481
2007 Msx2-interacting nuclear target protein (Mint) deficiency reveals negative regulation of early thymocyte differentiation by Notch/RBP-J signaling. Proceedings of the National Academy of Sciences of the United States of America 44 17242367
2007 The monolayer formation of Bergmann glial cells is regulated by Notch/RBP-J signaling. Developmental biology 44 17915208
2020 Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of RBPJ and p53. Oncogene 43 33311552
2016 Notch-independent RBPJ controls angiogenesis in the adult heart. Nature communications 43 27357444
2019 Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site. Cell reports 40 30673607
2013 The Prdm13 histone methyltransferase encoding gene is a Ptf1a-Rbpj downstream target that suppresses glutamatergic and promotes GABAergic neuronal fate in the dorsal neural tube. Developmental biology 40 24370451
2015 Epstein-Barr Virus Nuclear Antigen 3 (EBNA3) Proteins Regulate EBNA2 Binding to Distinct RBPJ Genomic Sites. Journal of virology 39 26719268
2022 Exosomal circRNA BTG2 derived from RBP-J overexpressed-macrophages inhibits glioma progression via miR-25-3p/PTEN. Cell death & disease 38 35643814
2003 Regulation of B cell development by Notch/RBP-J signaling. Seminars in immunology 37 12681948
2021 Transcription Factor RBPJ as a Molecular Switch in Regulating the Notch Response. Advances in experimental medicine and biology 36 33034023
2014 Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. The American journal of pathology 34 24631193
1995 Loss of immunostaining of the RBP-J kappa transcription factor upon F9 cell differentiation induced by retinoic acid. Journal of biochemistry 31 8690727
2017 Structure-function analysis of RBP-J-interacting and tubulin-associated (RITA) reveals regions critical for repression of Notch target genes. The Journal of biological chemistry 30 28487372
2021 LncRNA FTX Promotes Colorectal Cancer Cells Migration and Invasion by miRNA-590-5p/RBPJ Axis. Biochemical genetics 29 33389283
2021 Exosomal LncRNA LBX1-AS1 Derived From RBPJ Overexpressed-Macrophages Inhibits Oral Squamous Cell Carcinoma Progress via miR-182-5p/FOXO3. Frontiers in oncology 29 33816238
2016 An Intronic Flk1 Enhancer Directs Arterial-Specific Expression via RBPJ-Mediated Venous Repression. Arteriosclerosis, thrombosis, and vascular biology 29 27079877
2012 Requirements for Jag1-Rbpj mediated Notch signaling during early mouse lens development. Developmental dynamics : an official publication of the American Association of Anatomists 29 22275127
2018 Cyclin F-Dependent Degradation of RBPJ Inhibits IDH1R132H-Mediated Tumorigenesis. Cancer research 28 30254149
2010 The transcription factor RBP-J-mediated signaling is essential for dendritic cells to evoke efficient anti-tumor immune responses in mice. Molecular cancer 28 20420708
2022 Notch-dependent and -independent functions of transcription factor RBPJ. Nucleic acids research 27 35848919
2020 RBPJ contributes to the malignancy of glioblastoma and induction of proneural-mesenchymal transition via IL-6-STAT3 pathway. Cancer science 27 32885530
2021 Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ. Aging cell 26 33387451
2016 EBNA3C Directs Recruitment of RBPJ (CBF1) to Chromatin during the Process of Gene Repression in EBV Infected B Cells. PLoS pathogens 26 26751214
2007 Rbp-j regulates expansion of pancreatic epithelial cells and their differentiation into exocrine cells during mouse development. Developmental dynamics : an official publication of the American Association of Anatomists 26 17849436
2018 RBPJ mediates uterine repair in the mouse and is reduced in women with recurrent pregnancy loss. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 29242273
2015 Hypoxia but not normoxia promotes Smoothened transcription through upregulation of RBPJ and Mastermind-like 3 in pancreatic cancer. Cancer letters 24 26655998
2018 YAP Activation Drives Liver Regeneration after Cholestatic Damage Induced by Rbpj Deletion. International journal of molecular sciences 23 30501048
2009 RBP-J promotes neuronal differentiation and inhibits oligodendroglial development in adult neurogenesis. Developmental biology 23 19501584
2006 Epstein-Barr virus nuclear antigen 2 trans-activates the cellular antiapoptotic bfl-1 gene by a CBF1/RBPJ kappa-dependent pathway. Journal of virology 23 16873269
2012 Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice. PloS one 22 23110206
2016 Down-regulation of RBP-J mediated by microRNA-133a suppresses dendritic cells and functions as a potential tumor suppressor in osteosarcoma. Experimental cell research 21 27794430
2016 MicroRNA-133a-3p exerts inhibitory effects on gallbladder carcinoma via targeting RBPJ. American journal of cancer research 21 27904763
2020 Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ. Proceedings of the National Academy of Sciences of the United States of America 20 32075915
2019 Kruppel-like factor 4 regulates developmental angiogenesis through disruption of the RBP-J-NICD-MAML complex in intron 3 of Dll4. Angiogenesis 20 30607695
2017 In patients with chronic aplastic anemia, bone marrow-derived MSCs regulate the Treg/Th17 balance by influencing the Notch/RBP-J/FOXP3/RORγt pathway. Scientific reports 20 28195151
2013 Increased cAMP in monocytes augments Notch signaling mechanisms by elevating RBP-J and transducin-like enhancer of Split (TLE). The Journal of biological chemistry 20 23775085
2011 The role of the transcription factor Rbpj in the development of dorsal root ganglia. Neural development 20 21510873
2016 The Notch Intracellular Domain Has an RBPj-Independent Role during Mouse Hair Follicular Development. The Journal of investigative dermatology 19 26940862
2011 Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk. Journal of cell science 19 21558417
2019 Regulatory network mediated by RBP-J/NFATc1-miR182 controls inflammatory bone resorption. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 31908034