Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.
By D. Fingar, S. Salama, Christina Tsou, E. Harlow, J. Blenis. Genes & Development, 2002
1,118 citations recorded by the source corpus.
The coordinated action of cell cycle progression and cell growth (an increase in cell size and cell mass) is critical for sustained cellular proliferation, yet the biochemical signals that control cell growth are poorly defined, particularly in mammalian systems. We find that cell growth and cell cycle progression are separable processes in mammalian cells and that growth to appropriate cell size requires mTOR- and PI3K-dependent signals. Expression of a rapamycin-resistant mutant of mTOR rescues the reduced cell size phenotype induced by rapamycin in a kinase-dependent manner, showing the evolutionarily conserved role of mTOR in control of cell growth. Expression of S6K1 mutants that possess partial rapamycin-resistant activity or overexpression of eIF4E individually and additively partially rescues the rapamycin-induced decrease in cell size. In the absence of rapamycin, overexpression of S6K1 or eIF4E increases cell size, and, when coexpressed, they cooperate to increase cell size further. Expression of a phosphorylation site-defective mutant of 4EBP1 that constitutively binds the eIF4E-Cap complex to inhibit translation initiation reduces cell size and blocks eIF4E effects on cell size. These data show that mTOR signals downstream to at least two independent targets, S6K1 and 4EBP1/eIF4E, that function in translational control to regulate mammalian cell size.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/6c8b3d636155cbd7a2f1fd24ccb46273383f6a90
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Citations in the corpus
- Targeting PI3K/Akt signal transduction for cancer therapy (2021, background): “mTORC1 controls cell growth in part by phosphorylating S6 kinase 1 (S6K1) and eIF-4E-binding protein 1 (4EBP1), known regulators of protein synthesis.(83) Furthermore, mTORC1mediated signaling to HIF1α and LIPIN1 increases glucose metabolism and lipid synthesis, respectively.”
- mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4E (2004, background): “We also consistently noted that the combination of KD mTOR plus rapamycin more strongly inhibits 4E-BP1 phosphorylation, G1-phase progression, and cell size (13) compared to WT-mTOR plus rapamycin.”
- TSC2 mediates cellular energy response to control cell growth and survival. (2003, positive): “that TSC2 plays an important role in 2DG-induced cell size as previously reported (Figures 8A and 8B) (Fingar et al., 2002).”
- Control of Dendritic Arborization by the Phosphoinositide-3′-Kinase–Akt–Mammalian Target of Rapamycin Pathway (2005, methodology): “The QuickChange system was used to generate the following: HA-RasV12C40, -S35, and -G37 from pGW1-HA-RasV12; Arf6-WT by changing asparagine 27 of Arf6T27N back to threonine; Arf6-Q67L by substituting glutamine-67 in Arf6-WT into leucine; and 4EB-P1-AA by changing threonines 37 and 46 to alanines (Fi”
- Activation of the PI3K/Akt pathway and chemotherapeutic resistance. (2002, background): “By controlling protein synthesis, p70S6K and 4E-BP1 also control cell growth and hypertrophy (Fingar et al., 2002), which are obviously important processes for tumor growth.”
- The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. (2008, background): “Therefore mTORC1 activation promotes cell growth, at least in part, by increasing the anabolic process of protein synthesis through activation of S6K and inhibition of 4E-BP [41].”
- Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity (2004, methodology): “a, S6K1 Thr 389 and S6 Ser 240/244 phosphorylation in fat of wild-type mice maintained on a NCD (2) or HFD (þ) for 4 months.”
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- Bidirectional Transport of Amino Acids Regulates mTOR and Autophagy (2009, positive): “Compared to a nonsilencing siRNA, downregulation of mTOR results in approximately 10% reduction in cell size (Figures 5F and 5G) consistent with previous reports in mammalian cells (Fingar et al., 2002; Kim et al., 2002).”
- Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation (2014, positive): “In particular, mTORC1 phosphorylates two regulators of protein synthesis, the S6 kinase 1 (S6K1, also known as p70 S6K) and 4 elongation factor-binding protein 1 (4E-BP1), thereby promoting cell growth and proliferation (Fingar et al., 2002; Holz and Blenis, 2005; Sarbassov et al., 2005).”
- An Integrated Mechanistic Model of Pan-Cancer Driver Pathways Predicts Stochastic Proliferation and Death (2017, background): “This is accomplished by mTORC1-mediated phosphorylation and inhibition of EIF4E-BP1 (Manning and Cantley, 2003), causing it to dissociate from and make available EIF4E, as well as its phosphorylation and activation of p70S6K (Fingar et al., 2002), which, when active, drives ribosome synthesis.”
- S6K1−/−/S6K2−/− Mice Exhibit Perinatal Lethality and Rapamycin-Sensitive 5′-Terminal Oligopyrimidine mRNA Translation and Reveal a Mitogen-Activated Protein Kinase-Dependent S6 Kinase Pathway (2004, background): “This conclusion stems from gene deletion studies with Drosophila (39) and with mice (51) as well as recent studies with cell cultures (11).”