Mechanisms of differentiation of U937 leukemic cells induced by GM-CSF and 1,25(OH)2 vitamin D3.
The human monoblast cell line, U937, was employed to elucidate early events associated with differentiation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) and 1,25-dihydroxy-Vitamin D3 (VD3). Exposure of cells to a combination of GM-CSF and VD3 resulted in an up-regulation of c-fos mRNA within 1 h and a marked down-regulation of c-myc mRNA by 24 h and this was associated with a shift of cell population from the S phase to the G0 + G1 phase of the cell cycle by 18%. This was followed by a marked enhancement of monocyte-associated cell surface antigens [OKM1 (CD11b), LeuM3 (CD14), M77.7], as determined by monoclonal antibodies and flow cytometry. Functional characteristics such as nitroblue-tetrazolium reduction, alpha-naphthyl butyrate esterase activity, and phagocytic capability occurred. Cells treated with GM-CSF or VD3 alone showed only minor changes. These results demonstrate a potent synergistic effect of GM-CSF and VD3 on induction of U937 differentiation. This differentiation was partially blocked by H7, a protein kinase C (PKC) inhibitor. Changes in c-myc and c-fos mRNA expressions and a shift in cell cycle were shown to be early events in this process.
Kim
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YR
Department of Cell Biology and Anatomy, New York Medical College, Valhalla 10595.
Abraham
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Lutton
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JD
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000951:Antigens, Neoplasm / Q000502:physiology; D000954:Antigens, Surface / Q000502:physiology; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000502:physiology; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation / Q000502:physiology
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D007546:Isoquinolines; D010879:Piperazines; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D002117:Calcitriol