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

By A. Y. Choo, Sang-Oh Yoon, Sang Gyun Kim, Philippe P Roux, J. Blenis. Proceedings of the National Academy of Sciences of the United States of America, 2008

856 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9e853553e5f16dafe44f0fda824c52d86b470877

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Citations in the corpus

mTOR signaling at a glance (2009, background): “In addition, recent reports suggest that important mTORC1 functions are resistant to inhibition by rapamycin (Choo et al., 2008; Feldman et al., 2009; Garcia-Martinez et al., 2009; Thoreen et al., 2009).”
mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. (2011, positive): “, 1995), does not inhibit 4E-BP1 phosphorylation equally well in all cell contexts despite invariantly promoting S6K1 dephosphorylation (Choo et al., 2008; Feldman et al., 2009; Thoreen et al., 2009).”
Rapamycin passes the torch: a new generation of mTOR inhibitors (2011, background): “For example, 4EBP1 is rephosphorylated and is refractory to long-term rapamycin treatment, even though S6K phosphorylation remains permanently inhibited under these condition”
DEPTOR is an mTOR Inhibitor Whose Frequent Overexpression in Multiple Myeloma Cells Promotes their Survival (2009, background): “However, both knockdowns also increased DEPTOR mRNA (Figure 4G), indicating that the regulation of DEPTOR mRNA expression by mTORC1 is rapamycin resistant, consistent with the increasing evidence that only some mTORC1 functions are sensitive to rapamycin (Choo et al., 2008; Feldman et al., 2009; Tho”
Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue (2013, background): “Rapamycin fails to inhibit mTORC1-mediated 4EBP1 phosphorylation in many contexts, suggesting mTORC1 uses discrete mechanisms or binding partners to interact with its substrates (32).”
mTOR: a pharmacologic target for autophagy regulation. (2015, positive): “Furthermore, rapamycin has differential effects on S6K and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two major mTORC1 substrates that regulate protein synthesis (103).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, neutral): “5B, Choo et al., 2008; Feldman et al., 2009; Kang et al., 2013; Thoreen et al., 2009).”