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 localization of 5' terminal oligopyrimidine (TOP-) mRNAs. It is known that, in vertebrates, the translation of this group of mRNAs is regulated according to the growth status of the cell. Mitogenic stimulation of quiescent cells induces a rapid recruitment of TOP mRNAs from translationally inactive light messenger ribonucleoprotein particles to polysomes. It was found that administration 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-dichloro-1-beta-D-ribofuranosylbenzimidazole caused a similar activation whereas alpha-amanitin or low doses of act D did not induce the translational response. Concentrations of act D sufficient to induce TOP mRNA translation also induce 40S ribosomal protein S6 kinases 1 (S6K1) activation. Moreover at these concentrations of act D increased phosphorylation of 4E-BP1 was also observed, indicating the involvement of FRAP/mTOR. Consistent with this observation, pretreatment of resting cells with rapamycin suppresses the activation of TOP mRNA translation induced by act D. These results indicate that the effect of act D on translation is mediated by the S6Ks through FRAP/mTOR.
Loreni
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Dipartimento di Biologia, Universita' 'Tor Vergata', Roma, Italy; Department of Growth Control, Friedrich Miescher Institut, Basel, Switzerland. loreni@uniroma2.it
Thomas
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Amaldi
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D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004789:Enzyme Activation; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic / Q000187:drug effects*; D014714:Vertebrates; D029867:Xenopus Proteins; D014982:Xenopus laevis
D000546:Amanitins; D018797:Cell Cycle Proteins; D003839:Deoxyadenosines; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D029867:Xenopus Proteins; D003609:Dactinomycin; D004004:Dichlororibofuranosylbenzimidazole; D011494:Protein Kinases; C576898:Atr protein, Xenopus; D017853:Phosphotransferases (Alcohol Group Acceptor); D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C058120:cordycepin