Transcription inhibitors stimulate translation of 5 ' TOP mRNAs through activation of S6 kinase and the mTOR/FRAP signalling pathway

We have analysed the effect of transcription inhibitors on the polysomal lo calization of 5' terminal oligopyrimidine (TOP-) mRNAs. It is known that, i n vertebrates, the translation of this group of mRNAs is regulated accordin g to the growth status of the cell. Mitogenic stimulation of quiescent cell s induces a rapid recruitment of TOP mRNAs from translationally inactive li ght messenger ribonucleoprotein particles to polysomes. It was found that a dministration of transcription inhibitors to resting cells causes a similar collective translational activation of TOP mRNAs, without affecting global translation. A number of transcription inhibitors were tested in amphibian and mammalian cultured cells. Actinomycin D (act D), cordycepin, and 5,6-d ichloro-1-beta -d-ribofuranosylbenzimidazole caused a similar activation wh ereas alpha -amanitin or low doses of act D did not induce the translationa l response. Concentrations of act D sufficient to induce TOP mRNA translati on also induce 40S ribosomal protein S6 kinases 1 (S6K1) activation. Moreov er at these concentrations of act D increased phosphorylation of 4E-BP1 was also observed, indicating the involvement of FRAP/mTOR. Consistent with th is observation, pretreatment of resting cells with rapamycin suppresses the activation of TOP mRNA translation induced by act D. These results indicat e that the effect of act D on translation is mediated by the S6Ks through F RAP/mTOR.