Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation

AY Choo, SO Yoon, SG Kim… - Proceedings of the …, 2008 - National Acad Sciences
AY Choo, SO Yoon, SG Kim, PP Roux, J Blenis
Proceedings of the National Academy of Sciences, 2008National Acad Sciences
The mammalian translational initiation machinery is a tightly controlled system that is
composed of eukaryotic initiation factors, and which controls the recruitment of ribosomes to
mediate cap-dependent translation. Accordingly, the mTORC1 complex functionally controls
this cap-dependent translation machinery through the phosphorylation of its downstream
substrates 4E-BPs and S6Ks. It is generally accepted that rapamycin, a specific inhibitor of
mTORC1, is a potent translational repressor. Here we report the unexpected discovery that …
The mammalian translational initiation machinery is a tightly controlled system that is composed of eukaryotic initiation factors, and which controls the recruitment of ribosomes to mediate cap-dependent translation. Accordingly, the mTORC1 complex functionally controls this cap-dependent translation machinery through the phosphorylation of its downstream substrates 4E-BPs and S6Ks. It is generally accepted that rapamycin, a specific inhibitor of mTORC1, is a potent translational repressor. Here we report the unexpected discovery that rapamycin's ability to regulate cap-dependent translation varies significantly among cell types. We show that this effect is mechanistically caused by rapamycin's differential effect on 4E-BP1 versus S6Ks. While rapamycin potently inhibits S6K activity throughout the duration of treatment, 4E-BP1 recovers in phosphorylation within 6 h despite initial inhibition (1–3 h). This reemerged 4E-BP1 phosphorylation is rapamycin-resistant but still requires mTOR, Raptor, and mTORC1's activity. Therefore, these results explain how cap-dependent translation can be maintained in the presence of rapamycin. In addition, we have also defined the condition by which rapamycin can control cap-dependent translation in various cell types. Finally, we show that mTOR catalytic inhibitors are effective inhibitors of the rapamycin-resistant phenotype.
National Acad Sciences