title: The Notch ligand, Delta-1, partially inhibits GM-CSF-induced differentiation and apoptosis along with reducing the cleavage of PARP in U937 cells.
abstract: Notch signaling plays an important role in the regulation of self-renewal and differentiation of hematopoietic cells. Human monoblastic U937 cells undergo differentiation into macrophage-like cells, growth suppression, and apoptosis following stimulation with GM-CSF. We examined the effects of Notch activation induced by Notch ligands on GM-CSF-induced differentiation and apoptosis in U937 cells. Furthermore, the molecular mechanism of the effects was investigated. A recombinant Notch ligand, Delta-1 protein did not affect the growth of U937 cells by itself. GM-CSF-induced growth suppression and apoptosis of U937 cells were partially rescued by incubation with Delta-1. Delta-1 also reduced the GM-CSF-induced differentiation. Incubation with Delta-1 did not affect the expression of GM-CSF receptor. GM-CSF stimulation induced the phosphorylation of ERK1/2 and STAT5 and the cleavage of caspase-8, which were not affected by Delta-1 incubation, either. GM-CSF stimulation induced the cleavage of PARP, which is the key molecule for differentiation and apoptosis. We found that incubation with Delta-1 significantly suppressed the GM-CSF-induced cleavage of PARP. Taken together, we found that Notch activation induced by Delta-1 partially inhibited GM-CSF-induced differentiation, growth suppression, and apoptosis, along with reducing the GM-CSF-induced cleavage of PARP. These findings suggest one of the mechanisms by which Notch activation inhibits differentiation and apoptosis.
authors.affiliation: Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Murata-Ohsawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Tohda
authors.forename: Seiji
authors.initials: S
authors.lastname: Sakano
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nara
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology*; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051880:Receptors, Notch; D011994:Recombinant Proteins / Q000494:pharmacology; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D020298:U937 Cells
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D008894:Milk Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D051880:Receptors, Notch; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C064045:delta protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011065:Poly(ADP-ribose) Polymerases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases