Interferon gamma abrogates the differentiation block in v-myc-expressing U-937 monoblasts.
Extensive studies suggest a role for the myc protooncogene family in the control of cell proliferation and differentiation in vertebrates. Previously, deregulated expression of exogenous myc genes has been shown to inhibit induced differentiation in Friend erythroleukemia (MEL) cells and in human monoblastic U-937 cells. To examine the nature of the block of phorbol 12-myristate 13-acetate-induced differentiation in v-myc-expressing U-937 cells, we have studied the effect of other inducers utilizing signal pathways distinct from phorbol 12-myristate 13-acetate (i.e., 1 alpha, 25-dihydroxycholecalciferol and retinoic acid). We show that v-myc also inhibits differentiation associated with these inducers. However, the v-myc-associated block of phorbol 12-myristate 13-acetate-, 1 alpha,25-dihydroxycholecalciferol-, and retinoic acid-induced differentiation retinoic acid-induced differentiation can be overcome by adding interferon gamma as a costimulatory factor. Costimulation with interferon gamma restores terminal differentiation, as shown by acquisition of a macrophage phenotype and an irreversible growth arrest in the G0/G1 phase of the cell cycle, but induces only limited differentiation on its own. The differentiation is accomplished without altering the expression or nuclear localization of the v-myc protein. These results argue against the widely held view that down-regulation of myc expression is a general prerequisite for terminal differentiation of hematopoietic cells and suggests that interferon gamma induces a signal(s) that circumvents the v-myc activity.
Oberg
F
F
Department of Pathology, Uppsala University, University Hospital, Sweden.
Larsson
L G
LG
Anton
R
R
Nilsson
K
K
D015152:Blotting, Northern; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002762:Cholecalciferol / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D015870:Gene Expression; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology*; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016274:Oncogene Protein p55(v-myc); D012333:RNA, Messenger; D002762:Cholecalciferol; D014212:Tretinoin; D007371:Interferon-gamma; D004247:DNA; D013755:Tetradecanoylphorbol Acetate