Recombination signal-binding protein for immunoglobulin kappa J region (RBPJ)

Recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a highly conserved DNA-binding protein that serves as the essential transcriptional mediator of the Notch signaling pathway (UniProt P23508). In its default state, RBPJ acts as a transcriptional repressor by recruiting co-repressor complexes, such as SHARP and histone deacetylases, to the promoters of Notch target genes (PubMed: 22100035). Upon Notch receptor activation, the Notch intracellular domain (NICD) translocates to the nucleus and binds to RBPJ, displacing repressors and recruiting Mastermind-like (MAML) proteins to form an active transcriptional complex (NCBI Gene ID: 3516). This molecular switch is critical for regulating cell fate, differentiation, and proliferation in various tissues, including the immune and nervous systems. Dysregulation of RBPJ-mediated signaling is a hallmark of several malignancies, most notably T-cell acute lymphoblastic leukemia (T-ALL), where it drives the expression of oncogenic targets like MYC (PubMed: 32366889). Because RBPJ acts as a bottleneck for all four Notch receptors, it has emerged as a high-value therapeutic target for small molecule inhibitors like CB-103, which aim to disrupt the Notch transcription complex more specifically than traditional gamma-secretase inhibitors (Cellestia Biotech). However, therapeutic targeting of RBPJ faces challenges due to its requirement in normal tissue homeostasis, particularly in the maintaining the intestinal epithelium.

Other names

RBP-JCBF1CSLRBPSUHIGKJRBKBF2J-kappa recombination signal-binding proteinCBF-1

Small molecule inhibition of the Notch Transcription Complex (NTC) by disrupting the protein-protein interaction between RBPJ, the Notch intracellular domain (NICD), and Mastermind-like (MAML) co-activators, or by competitively inhibiting RBPJ DNA binding.