NICD1 produced by activation of NOTCH1 in response to Delta and Jagged ligands (DLL/JAG) presented in trans, traffics to the nucleus where it acts as a transcription regulator. In the nucleus, NICD1 displaces the NCOR corepressor complex from RBPJ (CSL). When bound to the co-repressor complex that includes NCOR proteins (NCOR1 and NCOR2) and HDAC histone deacetylases, RBPJ (CSL) represses transcription of NOTCH target genes (Kao et al. 1998, Zhou et al. 2000, Perissi et al. 2004, Perissi et al. 2008). Once the co-repressor complex is displaced, NICD1 recruits MAML (mastermind-like) to RBPJ, while MAML recruits histone acetyltransferases EP300 (p300) and PCAF, resulting in formation of the NOTCH coactivator complex that activates transcription from NOTCH regulatory elements. The minimal functional NOTCH coactivator complex that activates transcription from NOTCH regulatory elements is a heterotrimer composed of NICD, MAML and RBPJ (Fryer et al. 2002, Wallberg et al. 2002, Nam et al. 2006).
NOTCH1 coactivator complex is known to activate transcription of HES1 (Jarriault et al. 1995), HES5 (Arnett et al. 2010), HEY genes (Fischer et al. 2004, Leimeister et al. 2000, Maier et al. 2000, Arnett et al. 2010) and MYC (Palomero et al. 2006) and likely regulates transcription of many other genes (Wang et al. 2011). NOTCH1 coactivator complex on any specific regulatory element may involve additional transcriptional regulatory proteins. HES1 binds TLE proteins, forming an evolutionarily conserved transcriptional corepressor involved in regulation of neurogenesis, segmentation and sex determination (Grbavec et al. 1996, Fisher et al. 1996, Paroush et al. 1994).
After NOTCH1 coactivator complex is assembled on a NOTCH-responsive promoter, MAML (mastermind-like) recruits CDK8 in complex with cyclin C, triggering phosphorylation of conserved serine residues in TAD and PEST domains of NICD1 by CDK8. Phosphorylated NICD1 is recognized by the E3 ubiquitin ligase FBXW7 which ubiquitinates NICD1, leading to degradation of NICD1 and downregulation of NOTCH1 signaling. FBXW7-mediated ubiquitination and degradation of NOTCH1 depend on C-terminally located PEST domain sequences in NOTCH1 (Fryer et al. 2004, Oberg et al. 2001, Wu et al. 2001). The PEST domain of NOTCH1 and the substrate binding WD40 domain of FBXW7 are frequent targets of mutations in T-cell acute lymphoblastic leukemia - T-ALL (Welcker and Clurman 2008).
NICD1, which normally has a short half-life, can be stabilized by binding to the hypoxia-inducable factor 1-alpha (HIF1A) which accumulates in the nucleus when oxygen levels are low. This results in HIF1A-induced inhibition of cellular differentiation that is NOTCH-dependent (Gustafsson et al. 2005).
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