Disease relevance of RBPJ

• Epstein-Barr virus immortalization: Notch2 interacts with CBF1 and blocks differentiation [1].
• The regulation of K14/vGPCR transcripts by RBP-J raises the possibility that other modulators of Notch signaling might be able to induce expression of this RNA outside the context of lytic KSHV replication [2].
• Neither EBNA2-TAT, nor a mutant peptide with a 2-aa substitution that was unable to block the EBNA2-CBF1 interaction, significantly affected the growth of non-EBNA2-expressing EBV(-) B cells or Burkitt's lymphoma Akata cells [3].
• OBJECTIVES: To understand the functional consequences of a recurrent CADASIL mutation on furin processing, cell surface expression, ligand binding, and activation of a downstream effector CBF1 by the Notch3 receptor [4].
• Two immunogenic proteins of 27 (CBF1) and 29 (CBF2) kDa from enteropathogenic Campylobacter species appear to bind to mammalian cells [5].

High impact information on RBPJ

• EBNA2 is targeted to responsive promoters through interaction with a cellular DNA binding protein, C promoter binding factor 1 (CBF1) [6].
• CBF1 is identical to a protein thought to be involved in immunoglobulin gene rearrangement, RBPJ kappa [7].
• Moreover, we show that coexpression with MAM and CBF1 strongly enhances phosphorylation and proteolytic turnover of the Notch ICD in vivo [8].
• Activation of the Notch-regulated transcription factor CBF1/RBP-Jkappa through the 13SE1A oncoprotein [9].
• Similarly, the Epstein Barr viral oncoprotein EBNA2, which is required for B-cell immortalization, activates genes through CBF1 [9].

Chemical compound and disease context of RBPJ

• With the use of Epstein-Barr virus (EBV)-infected B cells as a model for CBF1 mediated CD23a expression, C1 was found to be EBV inducible [10].

Biological context of RBPJ

• CBF1 is a member of the CSL family of DNA binding factors, which mediate either transcriptional repression or transcriptional activation [11].
• The Epstein-Barr virus-immortalizing protein EBNA2 activates both cellular and viral gene expression by targeting CBF1 and mimicking NotchIC [11].
• We identified SKIP (Ski-interacting protein) as a CBF1 binding protein in a yeast two-hybrid screen [12].
• This activated form of Notch2 transactivated expression of a target gene containing upstream CBF1 binding sites [1].
• The use of CBF1 mutants carrying amino acid substitutions in the transcriptional repression domain revealed that activation of gene expression by Notch2 is also based on masking of CBF1-mediated repression [1].

Anatomical context of RBPJ

• Notch-mediated CBF-1/RBP-J{kappa}-dependent regulation of human vascular smooth muscle cell phenotype in vitro [13].
• We speculate that the Notch4/Int3 ICD-induced block to mammary gland development and tumorigenesis are consequences of an increasing gradient of CBF1-dependent Notch4/Int3 signaling [14].
• Here, we have tested this hypothesis by examining KSHV infection of RBP-J kappa-null murine fibroblasts [15].
• In this paper,we show that CBF1 from cell lines of different origin is able to bind to the[kappa]B site of the IL-6 promoter [16].
• When epithelial stem cells were plated on the bound ligand, the Notch/CBF-1 signaling pathway was stimulated and the cells upregulated both intermediate- and late-stage differentiation markers [17].

Associations of RBPJ with chemical compounds

• Notch1 signaling, assessed by measuring the activity of CBF1, a downstream transcription factor, was impaired but not abolished by the PS1 aspartate mutations or gamma-secretase inhibitors [18].
• N1(deltaEC) dramatically increased chloramphenicol acetyltransferase activity in these cells, indicating functional coupling of Notch1 and CBF1 [19].
• The EBNA2-TAT peptide blocked EBNA2-CBF1 interaction in an in vitro GST affinity assay and labeling with fluorescein confirmed that the EBNA2-TAT peptide efficiently entered cultured B cells [3].
• By electrophoretic mobility shift assays, we identified a transcription factor complex (C1) that binds sequence specific to one known and 4 newly identified putative CBF1 recognition sites in the CD23a core promoter region [10].
• We further show that ABA induces the expression of Cat1 via the interaction between ABRE2 and one of its binding proteins, CBF1 (Cat1 binding factor 1) [20].

Physical interactions of RBPJ

• The cleaved intracellular region (RAMIC) of Notch is translocated into the nucleus and interacts with a DNA-binding protein RBP-J to activate transcription of genes that regulate cell differentiation [21].
• Mobility shift assays and supershift assays demonstrated that CBF-1 binds to the PTEN minimal promoter [22].

Regulatory relationships of RBPJ

• These findings suggest that Notch promotes changes in hVSMC phenotype via activation of CBF-1/RBP-Jkappa-dependent pathways in vitro and contributes to the phenotypic response of VSMCs to cyclic strain-induced changes in VSMC differentiation [13].
• The transcription factor YY1 indirectly regulated the transcriptional activity of the wild-type CBF1-response elements via the direct interaction of N1IC and CBF1 [23].
• Moreover, we found that overexpression of RING1 together with KyoT2 in cells inhibited transactivation of RBP-J by NIC [24].

Other interactions of RBPJ

• CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex [11].
• The activated intracellular form of Notch, NotchIC, translocates to the nucleus, where it targets the DNA binding protein CBF1 [12].
• In competition binding experiments SMRT displaced NotchIC from CBF1 and from SKIP [12].
• These results support a model in which the binding of NIC-1 to CBF1 is required for AP-1 repression and reveal a powerful cell-sensing mechanism that suppresses the levels of transcriptionally competent NIC-1 [25].
• c-Myc substitutes for Notch1-CBF1 functions in cooperative transformation with papillomavirus oncogenes [26].

Analytical, diagnostic and therapeutic context of RBPJ

• However, in the present study we showed by in situ hybridization with the functional KBF2/RBPJk cosmid clone that the gene is localized at 9p12-13 and 9q13, namely, at the same loci as pseudogenes that were reported previously (Zhang et al, Jpn J Human Genet 39, 391-401, 1994) [27].
• Further studies, including site-directed mutagenesis experiments, narrowed down the region of mouse Notch1 that interacts with RBP-J kappa [28].
• Immunoprecipitation analysis showed that RBP-J kappa and the mRAM23 region of mouse Notch1 also interact in vivo [28].
• Accordingly, EBNA2 targeted CBF1 binding sites present in the FcRH5 promoter in vivo, as detected by chromatin immunoprecipitation [29].
• Analysis of whole-cell extracts from 14 strains by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis with 7 M urea and immunoblotting with antisera to CBF1 and CBF2 suggests that CBF proteins from adherent and nonadherent strains are different [5].

References