Transient inhibition of protein synthesis induces expression of proto-oncogenes and stimulates resting cells to enter the cell cycle.
There is evidence that resting cells are able to produce molecules with antiproliferative activity, some of which behave as short-lived repressor proteins. We suggest that transient inhibition of protein synthesis in resting cells would lead to a decrease in the levels of these negative growth regulators and might, therefore, promote mitogenic responses. We report that treatment of resting (serum-deprived) NIH 3T3 cells with cyclocheximide (CH) or puromycin induces expression of c-fos, c-jun and c-myc proto-oncogenes in a manner similar to that of platelet-derived growth factor (PDGF). Actinomycin D (Act D) abrogates the induction of proto-oncogene expression. Transient inhibition of protein synthesis by CH or puromycin also induces the resting NIH 3T3 and C3H 1OT1/2 cells to enter the cell cycle. Inhibition of new RNA or protein synthesis abolishes the proliferative response. These findings show that control mechanisms at both transcriptional and translational levels are operative in the resting cells treated with protein synthesis inhibitors. Cell fusion experiments with resting and serum-stimulated NIH 3T3 cells revealed that brief pre-incubation of resting cells with either PDGF, CH or puromycin abrogates their ability to suppress the onset of DNA synthesis in the nuclei of stimulated cells in heterodikaryons. However, the abrogative effect of PDGF disappeared in the presence of Act D, whereas the effects of protein synthesis inhibitors did not, indicating their independence of the induction of transcription. The data suggest that the observed effects of protein synthesis inhibitors are connected with elimination of some short-lived negative growth regulators, since a brief translational arrest is sufficient for the resumption of DNA synthesis in the nuclei of stimulated cells blocked by resting cells in heterodikaryons.
Rosenwald
I B
IB
Harvard-MIT Division of Health Sciences and Technology, Cambridge, USA.
Setkov
N A
NA
Kazakov
V N
VN
Chen
J J
JJ
Ryazanov
A G
AG
London
I M
IM
Epifanova
O I
OI
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos; D016758:Genes, jun; D016259:Genes, myc; D006822:Hybrid Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011519:Proto-Oncogenes; D011691:Puromycin / Q000494:pharmacology*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D010982:Platelet-Derived Growth Factor; D011500:Protein Synthesis Inhibitors; D012097:Repressor Proteins; D003609:Dactinomycin; D011691:Puromycin; D003513:Cycloheximide