Notch 1 and 3 receptors modulate 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.

YB-1 Acts as a Ligand for Notch-3 Receptors and Modulates Receptor Activation

“…Furthermore, Notch-1 and Notch-3 appear to behave very similarly in terms of interaction with the conventional Notch DSL ligands, i.e. Jagged1 and Delta-like-1 (35). Our data show that the EGF-like repeats 13-33 in Notch-3 are sufficient for interaction with YB-1.…”

Physiology and pathology of notch signalling system

“…As described by Campos et al (2002), also here Notch3 modulates c-FLIP expression by the ERK/ mitogen-activated protein kinase (MAPK) cascade. In a very recent study (Sweeney et al, 2004) the capacity of Notch1 and Notch3 to modulate apoptosis in VSMC by the classic RBP-Jk-dependent mechanism was shown. In another paper, Wang et al (2003) showed that inhibition of apoptosis in VSMC might occur by mechanisms not involving c-FLIP.…”

Canonical Notch signaling is not required for the growth of Hedgehog pathway-induced medulloblastoma

“…There is some emerging genetic evidence to suggest the existence of an RBP-J-independent ('non-canonical') pathway through which Notch receptor signaling may exert some influence (Talora et al, 2008). However, the key effectors implicated in medulloblastoma growth, Hes1 and Hes5 are clearly both 'canonical' Notch targets (Jarriault et al, 1995(Jarriault et al, , 1998Sweeney et al, 2004;Ong et al, 2006). Given the number of ligands and receptors potentially having a role in the cerebellum, here we took the approach of blocking Notch signaling by deleting the common pathway effector RBP-J, which has proved to be a highly effective strategy in analyses of Notch signaling (Fujikura et al, 2006;Komine et al, 2007).…”