When found in cis, HD and PEST domain mutations act synergis...

created [InstanceEdit:2894859] Orlic-Milacic, M, 2013-01-02
dbId 2894861
displayName When found in cis, HD and PEST domain mutations act synergis...
modified [InstanceEdit:2982611] Orlic-Milacic, M, 2013-01-14
schemaClass Summation
text 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.
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