title: A receptor-specific function for Notch2 in mediating vascular smooth muscle cell growth arrest through cyclin-dependent kinase inhibitor 1B.
abstract: BACKGROUND
  Deregulated vascular smooth muscle cell (VSMC) proliferation contributes to multiple vascular pathologies, and Notch signaling regulates VSMC phenotype.
  
  
  OBJECTIVE
  Previous work focused on Notch1 and Notch3 in VSMC during vascular disease; however, the role of Notch2 is unknown. Because injured murine carotid arteries display increased Notch2 in VSMC as compared with uninjured arteries, we sought to understand the impact of Notch2 signaling in VSMCs.
  
  
  RESULTS
  In human primary VSMCs, Jagged-1 (Jag-1) significantly reduced proliferation through specific activation of Notch2. Increased levels of p27(kip1) were observed downstream of Jag-1/Notch2 signaling and were required for cell cycle exit. Jag-1 activation of Notch resulted in increased phosphorylation on serine 10, decreased ubiquitination, and prolonged half-life of p27(kip1). Jag-1/Notch2 signaling robustly decreased S-phase kinase-associated protein, an F-box protein that degrades p27(kip1) during G1. Overexpression of S-phase kinase-associated protein before Notch activation by Jag-1 suppressed the induction of p27(kip1). Additionally, increased Notch2 and p27(kip1) expression was colocalized to the nonproliferative zone of injured arteries as indicated by co-staining with proliferating cell nuclear antigen, whereas Notch3 was expressed throughout normal and injured arteries, suggesting Notch2 may negatively regulate lesion formation.
  
  
  CONCLUSIONS
  We propose a receptor-specific function for Notch2 in regulating Jag-1-induced p27(kip1) expression and growth arrest in VSMCs. During vascular remodeling, colocalization of Notch2 and p27(kip1) to the nonproliferating region supports a model where Notch2 activation may negatively regulate VSMC proliferation to lessen the severity of the lesion. Thus, Notch2 is a potential target for control of VSMC hyperplasia.
authors: From the Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME.
authors: Joshua M
authors: JM
authors: Boucher
authors: Anne
authors: A
authors: Harrington
authors: Bahman
authors: B
authors: Rostama
authors: Volkhard
authors: V
authors: Lindner
authors: Lucy
authors: L
authors: Liaw
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C436291:CDKN1B protein, human; D002135:Calcium-Binding Proteins; C493961:Cdkn1b protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497764:NOTCH2 protein, human; C497765:Notch2 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D051883:Receptor, Notch2; D044786:S-Phase Kinase-Associated Proteins; D000072099:Serrate-Jagged Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: carotid intima-media thickness; cell proliferation; receptors, Notch; smooth muscle; vascular intima
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