title: 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.
authors.affiliation: Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ilona
authors.initials: I
authors.lastname: Patursky-Polischuk
authors.forename: Miri
authors.initials: M
authors.lastname: Stolovich-Rain
authors.forename: Mirit
authors.initials: M
authors.lastname: Hausner-Hanochi
authors.forename: Judith
authors.initials: J
authors.lastname: Kasir
authors.forename: Nadine
authors.initials: N
authors.lastname: Cybulski
authors.forename: Joseph
authors.initials: J
authors.lastname: Avruch
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.forename: Oded
authors.initials: O
authors.lastname: Meyuhas
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D038641:RNA 5' Terminal Oligopyrimidine Sequence / Q000235:genetics*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076205:Ras Homolog Enriched in Brain Protein; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D009479:Neuropeptides; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C525637:rictor protein, mouse; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus