mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs

By R. Dowling, I. Topisirovic, T. Alain, M. Bidinosti, Bruno D Fonseca, E. Petroulakis, Xiaoshan Wang, O. Larsson, A. Selvaraj, Yi Liu and 3 more. Science, 2010

726 citations recorded by the source corpus.

Proliferation Control The protein complex mTORC1, which contains the protein kinase known as mammalian target of rapamycin, is an important regulator of cell proliferation and cell size. Among many targets, mTORC1 phosphorylates the eukaryotic translation initiation factor eIF4E–binding proteins (4E-BPs), thus controlling translation of proteins that regulate proliferation. Dowling et al. (p. 1172) used mice lacking expression of the 4E-BPs to show that these proteins contribute to mTORC1's activation of cell proliferation, but are dispensable for the effects of mTORC1 on cell growth. The latter required another mTORC1 target—the ribosomal protein S6 kinase. mTORC1 inhibitors are being explored as potential anticancer agents, and the presence of 4E-BPs was necessary for mTORC1 inhibitors to reduce the number and size of colonies formed by transformed mouse cells. Control of cell proliferation and cell size is separately regulated in mammals. The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. Hence, mTORC1 is implicated in a large number of human diseases—including diabetes, obesity, heart disease, and cancer—that are characterized by aberrant cell growth and proliferation. Although eukaryotic translation initiation factor 4E–binding proteins (4E-BPs) are critical mediators of mTORC1 function, their precise contribution to mTORC1 signaling and the mechanisms by which they mediate mTORC1 function have remained unclear. We inhibited the mTORC1 pathway in cells lacking 4E-BPs and analyzed the effects on cell size, cell proliferation, and cell cycle progression. Although the 4E-BPs had no effect on cell size, they inhibited cell proliferation by selectively inhibiting the translation of messenger RNAs that encode proliferation-promoting proteins and proteins involved in cell cycle progression. Thus, control of cell size and cell cycle progression appear to be independent in mammalian cells, whereas in lower eukaryotes, 4E-BPs influence both cell growth and proliferation.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c6d5f3c46a728fd7964a774b1a2baa8ba0fd1622

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Citations in the corpus

mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. (2013, methodology): “Cell Culture, Lentivirus shRNA Silencing, and mTOR Inhibitors Cell culture and lentivirus shRNA silencing were carried out as described (Dowling et al., 2010).”
The PI3K pathway in human disease (2017, positive): “In ﬁbroblasts, mTORC1 promotes cell size increase mainly through S6Ks while driving cell-cycle progression mainly through the 4E-BP/eIF4E axis (Dowling et al., 2010).”
mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. (2011, positive): “In addition to translation, catalytic site mTOR inhibitors, also potently regulate other known outputs of mTORC1 signaling, such as autophagy and proliferation, to a greater degree than rapamycin does (Dowling et al., 2010; Feldman et al., 2009; Thoreen et al., 2009).”
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype (2015, neutral): “Thismaybeexplainedbythewelldescribed antiproliferative eﬀects caused by mTOR inhibition 30,31 .”
Human eIF4E promotes mRNA restructuring by stimulating eIF4A helicase activity (2013, background): “The overwhelming majority of these mRNAs possess long structured 5′-UTRs that must be unwound to allow ribosome recruitment and scanning (2, 5, 7, 8).”
mTOR signaling in growth control and disease (2012, background): “Loss of 4EBP1/2 and the concomitant activation of cap-dependent translation promotes cell-cycle progression and cell proliferation in culture (Dowling et al., 2010).”