description
When found in cis, HD and PEST domain mutations act synergistically, increasing NOTCH1 transcriptional activity up to ~40-fold, compared with up to ~10-fold and up to ~2-fold increase with HD mutations alone and PEST domain mutations alone, respectively (Weng et al. 2004). HD domain mutations enable spontaneous, ligand-independent, proteolytic release of the NICD1 fragment, although mutants remain responsive to ligand binding (Malecki et al. 2006), while PEST domain mutations prolong NICD1 half-life and transcriptional activity through interference with FBXW7 (FBW7)-mediated ubiquitination and degradation (Thompson et al. 2007, O'Neil et al. 2007). NOTCH1 HD+PEST domain mutants annotated here are NOTCH1 L1600P;P2514Rfs*4, NOTCH1 L1600P;Q2440*, NOTCH1 L1600P;Q2395* and NOTCH1 L1574P;P2474Afs*4

external resources
NCBI:1268891
REACTOME:R-HSA-2894862
PUBMED:15472075
PUBMED:17646408
PUBMED:17646409
PUBMED:16738328

genes
ADAM10 , JAG1 , CCNC , CDK8 , CREBBP , EP300 , KAT2A , HDAC1 , HDAC2 , HES1 , RBPJ , JAG2 , MYC , NOTCH1 , PSEN2 , RPS27A , SKP1 , ADAM17 , TBL1X , UBA52 , UBB , UBC , CUL1 , HDAC3 , KAT2B , NEURL1 , NCOR1 , NCOR2 , HDAC9 , HDAC4 , MAML1 , RBX1 , HDAC6 , HDAC5 , MAMLD1 , SNW1 , NCSTN , HEY1 , HEY2 , HEYL , DLL1 , APH1A , HDAC7 , NEURL1B , DLL4 , FBXW7 , MAML3 , PSENEN , HDAC8 , MIB1 , TBL1XR1 , HDAC11 , APH1B , HDAC10 , MAML2 , MIB2 , HES5 , MIR1281 ,