title: Notch 1 and 3 receptor signaling modulates vascular smooth muscle cell growth, apoptosis, and migration via a CBF-1/RBP-Jk dependent pathway.
abstract: Vascular smooth muscle cell (SMC) fate decisions (cell growth, migration, and apoptosis) are fundamental features in the pathogenesis of vascular disease. We investigated the role of Notch 1 and 3 receptor signaling in controlling adult SMC fate in vitro by establishing that hairy enhancer of split (hes-1 and -5) and related hrt's (hrt-1, -2, and -3) are direct downstream target genes of Notch 1 and 3 receptors in SMC and identified an essential role for nuclear protein CBF-1/RBP-Jk in their regulation. Constitutive expression of active Notch 1 and 3 receptors (Notch IC) resulted in a significant up-regulation of CBF-1/RBP-Jk-dependent promoter activity and Notch target gene expression concomitant with significant increases in SMC growth while concurrently inhibiting SMC apoptosis and migration. Moreover, inhibition of endogenous Notch mediated CBF-1/RBP-Jk regulated gene expression with a non-DNA binding mutant of CBF-1, a Notch IC deleted of its delta RAM domain and the Epstein-Barr virus encoded RPMS-1, in conjunction with pharmacological inhibitors of Notch IC receptor trafficking (brefeldin A and monensin), resulted in a significant decrease in cell growth while concomitantly increasing SMC apoptosis and migration. These findings suggest that endogenous Notch receptors and downstream target genes control vascular cell fate in vitro. Notch signaling, therefore, represents a novel therapeutic target for disease states in which changes in vascular cell fate occur in vivo.
authors.affiliation: Vascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin 9, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sweeney
authors.forename: David
authors.initials: D
authors.lastname: Morrow
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Birney
authors.forename: Seamus
authors.initials: S
authors.lastname: Coyle
authors.forename: Colm
authors.initials: C
authors.lastname: Hennessy
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Scheller
authors.forename: Philip M
authors.initials: PM
authors.lastname: Cummins
authors.forename: Dermot
authors.initials: D
authors.lastname: Walls
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Redmond
authors.forename: Paul A
authors.initials: PA
authors.lastname: Cahill
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020126:Brefeldin A / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D008985:Monensin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface / Q000378:metabolism; D051880:Receptors, Notch; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497763:Notch1 protein, rat; C498556:Notch3 protein, rat; D009687:Nuclear Proteins; C497572:Rbpjl2 protein, rat; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors; D020126:Brefeldin A; D008985:Monensin