Abstract
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-2alpha 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-2alpha phosphorylation in mammalian cells, which may not, however, be involved in TOP mRNA translational regulation.
Highlights
One of the strategies used by eukaryotic cells to maintain homeostatic steady state is to regulate the engagement of mRNAs in protein synthesis
They showed that the transduction of growth and mitogenic signals to terminal oligopyrimidine (TOP) mRNA translation depends on PI 3-kinase (PI3K), but does not require either S6K1 or RPS6 phosphorylation
The translation of three TOP mRNAs (RPS19, RPS6, and eukaryotic elongation factor-1␣) and three non-TOP mRNAs (-actin, superoxide dismutase, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) was assayed under the different culture conditions by the standard polysomal association technique, which measures the amount of mRNA associated with particles of different size
Summary
One of the strategies used by eukaryotic cells to maintain homeostatic steady state is to regulate the engagement of mRNAs in protein synthesis. We observed a good correlation between the changes in these two regulators and the decrease in polysomal association of TOP and non-TOP mRNAs, consistent with their role in translation and their regulation by the amino acid and serum-sensitive mTOR pathway.
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