Lack of requirement for presenilin1 in Notch1 signaling.
Studies in invertebrates have indicated a functional requirement for presenilin (PS) genes in the Notch pathway [1-5]. One model of Notch signal transduction suggests that proteolysis releases an activated Notch fragment that migrates to the nucleus and regulates gene transcription in concert with CBF1/Su(H)/lag1 (CSL) proteins [6-9]. Recent studies suggest that PS genes control the proteolysis and nuclear access of the Notch intracellular domain [3,4,10,11], offering a basis for the functional interaction of PS and Notch genes [12]. Here, we report that Notch1 signaling elicited by the ligand Delta1 was quantitatively unchanged in PS1-deficient primary embryonic fibroblasts (PEFs). Notch1 signals were measured by both the activation of the hairy/enhancer of split (HES1) promoter and by the antagonism of MyoD-induced muscle creatine kinase (MCK) promoter activity. A membrane-tethered ligand-independent Notch1 construct also showed full efficacy in both assays, despite its presumed requirement for cleavage. Although signaling through Notch1 persisted in PS1-deficient cells, we found a marked reduction in the appearance of a complex of a cleaved, intracellular Notch fragment (NICD) and 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 fragment may not be necessary for Notch signal transduction [9].
Berechid
B E
BE
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago 60611, USA.
Thinakaran
G
G
Wong
P C
PC
Sisodia
S S
SS
Nye
J S
JS
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001665:Binding Sites; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017570:MyoD Protein / Q000502:physiology; D053764:Presenilin-1; D053766:Presenilin-2; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014157:Transcription Factors
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D017570:MyoD Protein; D053764:Presenilin-1; D053766:Presenilin-2; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C489734:Hes1 protein, mouse; C497762:Notch1 protein, mouse; C064045:delta protein