Lack of requirement for Presenilin1 in Notch1 signaling

Studies in invertebrates have indicated a functional requirement for presen ilin (PS) genes in the Notch pathway [1-5], One model of Notch signal trans duction suggests that proteolysis releases an activated Notch fragment that migrates to the nucleus and regulates gene transcription in concert with C BF1/Su(H)/lag1 (CSL) proteins [6-9], Recent studies suggest that PS genes c ontrol the proteolysis and nuclear access of the Notch intracellular domain [3,4,10,11], offering a basis for the functional interaction of PS and Not ch genes [12]. Here, we report that Notch1 signaling elicited by the ligand Delta1 was quantitatively unchanged in PS1-deficient primary embryonic fib roblasts (PEFs), Notch1 signals were measured by both the activation of the hairy/enhancer of split (HES1) promoter and by the antagonism of MyoD-indu ced muscle creatine kinase (MCK) promoter activity. A membrane-tethered lig and-independent Notch1 construct also showed full efficacy in both assays, despite its presumed requirement for cleavage. Although signaling through N otch1 persisted in PS1 deficient cells, we found a marked reduction in the appearance of a complex of a cleaved, intracellular Notch fragment (NICD) a nd a CSL protein, as previously reported [6,10]. These studies reveal that PS1 is not required for ligand-dependent Notch signaling, and that PS1 and PS2 may be redundant, Our data also suggest that the identified NICD fragme nt may not be necessary for Notch signal transduction [9]. (C) 1999 Elsevie r Science Ltd. All rights reserved.