Notch1-mediated Notch Transcription Complex (Notch1-NTC)

The Notch1-mediated Notch Transcription Complex (NTC) is a nuclear multiprotein assembly that serves as the primary effector of the Notch1 signaling pathway. It is formed when the Notch1 receptor undergoes proteolytic cleavage by gamma-secretase, releasing the Notch1 intracellular domain (NICD1), which translocates to the nucleus to associate with the DNA-binding protein RBPJ (also known as CSL) and a co-activator of the Mastermind-like (MAML) family (Kovall, R. A., & Blacklow, S. C., 2010, Current Opinion in Structural Biology). This ternary complex recruits additional histone acetyltransferases to initiate the transcription of target genes such as HES1 and MYC, which are critical for cell proliferation and survival (Weng, A. P., et al., 2004, Science). In many cancers, particularly T-cell acute lymphoblastic leukemia (T-ALL), the complex is constitutively active due to mutations that stabilize NICD1 or enhance its production. Therapeutic targeting of the NTC involves either preventing its formation via gamma-secretase inhibitors or directly disrupting the protein-protein interactions within the complex using small molecules like CB-103 or stapled peptides (Lehal, R., et al., 2020, Molecular Cancer Therapeutics). However, clinical application is often limited by dose-dependent gastrointestinal toxicities resulting from the inhibition of Notch signaling in the intestinal epithelium.

Other names

Notch1/RBPJ/MAML complexNICD1/CSL/MAML ternary complexNotch1 transcriptional activator complexNICD1-mediated transcription complex

Direct inhibition of the protein-protein interactions between the Notch1 intracellular domain (NICD1), the DNA-binding protein RBPJ (CSL), and the co-activator MAML, or upstream inhibition of Notch1 cleavage by gamma-secretase to prevent complex assembly (Kovall, R. A., 2008, PubMed; Lehal, R., et al., 2020, Molecular Cancer Therapeutics).