Posttranscriptional regulation of cellular gene expression by the c-myc oncogene.
The c-myc oncogene has been implicated in the development of many different cancers, yet the mechanism by which the c-myc protein alters cellular growth control has proven elusive. We used a cDNA hybridization difference assay to isolate two genes, mr1 and mr2, that were constitutively expressed (i.e., deregulated) in rodent fibroblast cell lines immortalized by transfection of a viral promoter-linked c-myc gene. Both cDNAs were serum inducible in quiescent G0 fibroblasts, suggesting that they are functionally related to cellular proliferative processes. Although there were significant differences in cytoplasmic mRNA levels between myc-immortalized and control cells, the rates of transcription and mRNA turnover of both genes were similar, suggesting that c-myc regulates mr1 and mr2 expression by some nuclear posttranscriptional mechanism. mr1 was also rapidly (within 2 h) and specifically induced by dexamethasone in BALB/c cell lines expressing a mouse mammary tumor virus long terminal repeat-driven myc gene, under conditions where other growth factor-inducible genes were unaffected. A frameshift mutation in the mouse mammary tumor virus myc gene destroyed the dexamethasone stimulation of mr1, indicating that c-myc protein is required for the effect. As in the myc-immortalized cells, the induction of mr1 by c-myc occurred without detectable changes in mr1 transcription or cytoplasmic mRNA stability, implicating regulation, either direct or indirect, through a nuclear posttranscriptional mechanism. These results provide evidence that c-myc can rapidly modulate cellular gene expression and suggest that c-myc may function in gene regulation at the level of RNA export, splicing, or nuclear RNA turnover.
Prendergast
G C
GC
Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, New Jersey 08544.
Cole
M D
MD
D000818:Animals; D003001:Cloning, Molecular; D004247:DNA / Q000302:isolation & purification; D004274:DNA, Recombinant / Q000032:analysis; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011519:Proto-Oncogenes; D012313:RNA / Q000032:analysis; D012323:RNA Processing, Post-Transcriptional
D004274:DNA, Recombinant; D006133:Growth Substances; D012313:RNA; D004247:DNA