title: Induced neuroblastoma cell differentiation, associated with transient HES-1 activity and reduced HASH-1 expression, is inhibited by Notch1.
abstract: Neuroblastoma is a childhood tumor that originates from the sympathetic nervous system. The tumor cells have embryonic features, presumably as a consequence of an impaired capacity to respond to signals and transcriptional control mechanisms operating during normal differentiation. Two basic helix-loop-helix transcription factors, human achaete-scute homologue-1 (HASH-1) and hairy/enhancer of split homologue-1 (HES-1), are crucial for proper development of some neuronal cells. Here, their potential roles during sympathetic differentiation of human neuroblastoma cells have been investigated. In all tested protocols for induction of differentiation of SH-SY5Y and SK-N-BE(2) neuroblastoma cells, HASH-1 expression was rapidly decreased with a concomitant, often transient, increase in HES-1 expression. In gel mobility shift assays, using extracts from neuroblastoma cells, HES-1 bound to an oligonucleotide corresponding to a sequence in the HASH-1 promoter including the so-called N-box, suggesting that the transiently increased HES-1 activity in differentiating neuroblastoma cells is involved in down-regulation of HASH-1. Constitutive expression of the intracellular domain of Notch1, which activates the HES-1 promoter in SH-SY5Y cells, inhibited spontaneous and induced morphological differentiation of these neuroblastoma cells. Our data show that functional sympathetic neuronal differentiation of neuroblastoma cells is associated with transient activation of HES-1 and down-regulation of HASH-1 expression.
authors.affiliation: Department of Laboratory Medicine, Molecular Medicine, University Hospital MAS, Lund University, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Grynfeld
authors.forename: S
authors.initials: S
authors.lastname: Påhlman
authors.forename: H
authors.initials: H
authors.lastname: Axelson
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D009447:Neuroblastoma / Q000473:pathology*; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C497761:NOTCH1 protein, human; C089199:ac protein, Drosophila; C078493:HES1 protein, human