The TSC-mTOR Pathway Mediates Translational Activation of TOP mRNAs by Insulin Largely in a Raptor- or Rictor-Independent Manner

Abstract

The stimulatory effect of insulin on protein synthesis is due to its ability to activate various translation factors. We now show that insulin can increase protein synthesis capacity also by translational activation of TOP mRNAs encoding various components of the translation machinery. This translational activation involves the tuberous sclerosis complex (TSC), as the knockout of TSC1 or TSC2 rescues TOP mRNAs from translational repression in mitotically arrested cells. Similar results were obtained upon overexpression of Rheb, an immediate TSC1-TSC2 target. The role of mTOR, a downstream effector of Rheb, in translational control of TOP mRNAs has been extensively studied, albeit with conflicting results. Even though rapamycin fully blocks mTOR complex 1 (mTORC1) kinase activity, the response of TOP mRNAs to this drug varies from complete resistance to high sensitivity. Here we show that mTOR knockdown blunts the translation efficiency of TOP mRNAs in insulin-treated cells, thus unequivocally establishing a role for mTOR in this mode of regulation. However, knockout of the raptor or rictor gene has only a slight effect on the translation efficiency of these mRNAs, implying that mTOR exerts its effect on TOP mRNAs through a novel pathway with a minor, if any, contribution of the canonical mTOR complexes mTORC1 and mTORC2. This conclusion is further supported by the observation that raptor knockout renders the translation of TOP mRNAs rapamycin hypersensitive.

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

“…Although both S6K and 4E-BP initiate translation in response to mTOR activation, they seem to act on specific mRNA populations. Although this view has been challenged recently [34], S6K is thought to specifically favour the translation of mRNA species containing an oligopyrimidine tract at the 5′ terminus (TOP-mRNAs), such as those encoding ribosomal proteins or elongation factors. The phosphorylation and dissociation of 4E-BP from eukaryotic translation initiation factor 4E (eIF-4E) allows the translation of cap-containing mRNAs and of mRNAs with 5′ secondary structures, which frequently encode proteins involved in proliferation [35].…”

Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

“…These studies suggested that mTOR functions in adult skeletal muscle require only mTORC1 (Bentzinger et al, 2008). However, there is evidence that some functions of mTOR, such as the activation of terminal oligopyrimidine mRNA translation, could be independent of mTORC1 and mTORC2 (Patursky-Polischuk et al, 2009).…”

miR-10 in development and cancer

“…In the event of stresses, such as amino acid starvation, TOP mRNAs are selectively repressed at the level of translation. 45,46 The upstream regulatory pathways regulating TOP translation involves the phosphatidylinositol 3-kinase (PI3K) and mTOR pathways, 47,48 and several RNA-binding proteins have been proposed to regulate the translation of TOP mRNAs. [49][50][51] However, the exact mechanism and wiring of upstream pathways is still largely unresolved.…”