Transcriptional and post-transcriptional regulation of c-myc, c-myb, and p53 during proliferation and differentiation of murine erythroleukemia cells treated with DFMO and DMSO.
The proto-oncogenes myc, myb, and p53 produce nuclear proteins which have been implicated in the regulation of proliferation or differentiation in a number of systems. The expression of these proto-oncogenes was studied in murine erythroleukemia (MEL) cells during (i) normal replication, (ii) DMSO-induced differentiation and (iii), alpha-difluoromethylornithine (DFMO)-restricted cell division and differentiation. The RNA levels of c-myc, c-myb, and p53 were all elevated during normal cellular proliferation; only c-myc expression declined when the cells stopped dividing although the rate of transcription for the gene was unaltered. In contrast, treatment of the cells with DFMO resulted in gradual cessation of cell replication and a decrease in transcription of c-myc, c-myb and p53. When the MEL cells were induced to differentiate with dimethyl sulfoxide (DMSO), a transient reduction in c-myc and c-myb RNA levels occurred immediately prior to the G1 arrest with a concomitant decrease in transcriptional activity, while p53 mRNA production was elevated without an increase in transcription. Similar changes of the proto-oncogene levels were observed when the MEL cells were incubated with DFMO and then later induced with DMSO, a protocol which restricts differentiation of the MEL cells. From these experiments we conclude that (i) c-myc, c-myb, and p53 are regulated independently at both the transcriptional and post-transcriptional levels, (ii) DFMO inhibits MEL cell proliferation and expression of several genes, including c-myc, c-myb and p53, and (iii) DFMO suppresses terminal differentiation but is unable to alter proto-oncogene changes associated with the early stages of differentiation.
Klinken
S P
SP
Laboratory of Immunopathology, NIH, Bethesda, Maryland 20892.
Holmes
K L
KL
Morse
H C
HC
Thorgeirsson
S S
SS
D000818:Animals; D015152:Blotting, Northern; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D005786:Gene Expression Regulation; D004915:Leukemia, Erythroblastic, Acute; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D011519:Proto-Oncogenes; D012313:RNA / Q000032:analysis / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D012313:RNA; D004121:Dimethyl Sulfoxide; D000518:Eflornithine