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Science 328 (5982): 1172-1176

Copyright © 2010 by the American Association for the Advancement of Science

mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs

Ryan J. O. Dowling,1,*,{dagger} Ivan Topisirovic,1,* Tommy Alain,1 Michael Bidinosti,1 Bruno D. Fonseca,1 Emmanuel Petroulakis,1 Xiaoshan Wang,1 Ola Larsson,1 Anand Selvaraj,2 Yi Liu,3 Sara C. Kozma,2 George Thomas,2 Nahum Sonenberg1,{ddagger}

Abstract: 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.

1 Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
2 Department of Cancer and Cell Biology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
3 Intellikine, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} Present address: Division of Signalling Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada.

{ddagger} To whom correspondence should be addressed. E-mail: nahum.sonenberg{at}mcgill.ca

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