TRANSIENT INHIBITION OF PROTEIN-SYNTHESIS INDUCES EXPRESSION OF PROTOONCOGENES AND STIMULATES RESTING CELLS TO ENTER THE CELL-CYCLE

There is evidence that resting cells are able to produce molecules wit h antiproliferative activity, some of which behave as short-lived repr essor proteins. We suggest that transient inhibition of protein synthe sis in resting cells would lead to a decrease in the levels of these n egative growth regulators and might, therefore, promote mitogenic resp onses. We report that treatment of resting (serum-deprived) NIH 3T3 ce lls with cyclocheximide (CH) or puromycin induces expression of c-fos, c-jun and c-myc proto-oncogenes in a manner similar to that of platel et-derived growth factor (PDGF). Actinomycin D (Act D) abrogates the i nduction of proto-oncogene expression. Transient inhibition of protein synthesis by CH or puromycin also induces the resting NIH 3T3 and C3H 10T1/2 cells to enter the cell cycle. Inhibition of new RNA or protei n synthesis abolishes the proliferative response. These findings show that control mechanisms at both transcriptional and translational leve ls are operative in the resting cells treated with protein synthesis i nhibitors. Cell fusion experiments with resting and serum-stimulated N IH 3T3 cells revealed that brief pre-incubation of resting cells with either PDGF, CH or puromycin abrogates their ability to suppress the o nset of DNA synthesis in the nuclei of stimulated cells in heterodikar yons. However, the abrogative effect of PDGF disappeared in the presen ce of Act D, whereas the effects of protein synthesis inhibitors did n ot, indicating their independence of the induction of transcription. T he data suggest that the observed effects of protein synthesis inhibit ors 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.