title: Notch-independent regulation of Hes-1 expression by c-Jun N-terminal kinase signaling in human endothelial cells.
abstract: Our laboratory has recently demonstrated constitutive activation of the Notch signaling pathway in Kaposi's sarcoma tumor cells. As endothelial cells (EC) are believed to be the progenitor of these tumor cells, this study was designed to examine the effect of Notch activation on normal human EC. Recent reports suggest Notch activation induces EC growth arrest, and that this growth arrest may be linked to the establishment or maintenance of EC quiescence, the phenotype seen in contact-inhibited EC lining the vasculature. To gain further insight into Notch activation and quiescence, we first confirmed that Notch activation induced EC growth arrest. Next, we examined Notch activation in confluent, growth arrested EC (mimicking the cells lining the vasculature). In contrast to previous reports, we found confluent EC possess lower levels of activated Notch compared to proliferating control cells. Interestingly, these cells express elevated levels of Hes-1 protein (an immediate downstream target of Notch signaling) despite decreased Notch activation. Under these conditions, Hes-1 expression was mediated, at least in part, by a Notch-independent mechanism involving c-jun N-terminal protein kinase (JNK) signaling. This is the first report, to our knowledge, that JNK signaling can modulate Hes-1 expression in a Notch-independent manner.
authors.affiliation: Department of Pathology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153-5385, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Curry
authors.forename: Laura L
authors.initials: LL
authors.lastname: Reed
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nickoloff
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Foreman
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology; D034622:RNA Interference; D051880:Receptors, Notch / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human