Translational Regulation of Terminal Oligopyrimidine mRNAs Induced by Serum and Amino Acids Involves Distinct Signaling Events

Various mitogenic or growth inhibitory stimuli induce a rapid change in the association of terminal oligopyrimidine (TOP) mRNAs with polysomes. It is generally believed that such translational control hinges on the mammalian target of rapamycin (mTOR)-S6 kinase pathway. Amino acid availability affects the translation of TOP mRNAs, although the signaling pathway involved in this regulation is less well characterized. To investigate both serum- and amino acid-dependent control of TOP mRNA translation and the signaling pathways involved, HeLa cells were subjected to serum and/or amino acid deprivation and stimulation. Our results indicate the following. 1) Serum and amino acid deprivation had additive effects on TOP mRNA translation. 2) The serum content of the medium specifically affected TOP mRNA translation, whereas amino acid availability affected both TOP and non-TOP mRNAs. 3) Serum signaling to TOP mRNAs involved only a rapamycin-sensitive pathway, whereas amino acid signaling depended on both rapamycin-sensitive and rapamycin-insensitive but wortmannin-sensitive events. 4) Eukaryotic initiation factor-2α phosphorylation increased during amino acid deprivation, but not following serum deprivation. Interestingly, rapamycin treatment suggests a novel connection between the mTOR pathway and eukaryotic initiation factor-2α phosphorylation in mammalian cells, which may not, however, be involved in TOP mRNA translational regulation.