The proto-oncogene c-myc blocks myeloid differentiation independently of its target gene ornithine decarboxylase.
Ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, has been shown to be required for entry into and progression through the cell cycle and to be a transcriptional target of the proto-oncogene, c-myc. We show that ODC transcripts and enzyme activity are down-regulated following induction of myeloid differentiation, using M1 myeloblastic leukemic cells and normal cells from bone marrow (BM), and fail to be suppressed when c-myc expression is deregulated. In M1mycer cells, when endogenous c-myc expression has been suppressed following stimulation by interleukin-6 (IL-60), treatment with estrogen and cycloheximide results in induction of ODC transcripts. These data demonstrate that ODC is a c-myc target gene in M1 cells. It was of interest to determine whether deregulated ODC expression would alter the myeloid differentiation program. To answer this question, M1-ODC cell lines constitutively expressing ODC were established. These cells can undergo terminal differentiation and growth arrest following IL-6 stimulation, exactly like parental M1 cells, demonstrating that deregulated ODC expression is not sufficient to block myeloid differentiation. Another question to be answered was whether ODC expression is necessary for the c-myc-mediated block in differentiation. The use of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme activity, indicates that ODC is not necessary for the c-myc-mediated differentiation block.
Selvakumaran
M
M
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Liebermann
D
D
Hoffman
B
B
D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006410:Hematopoiesis; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D009955:Ornithine Decarboxylase / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D009955:Ornithine Decarboxylase