mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs.
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.
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Ryan J O
RJ
Dowling
Ivan
I
Topisirovic
Tommy
T
Alain
Michael
M
Bidinosti
Bruno D
BD
Fonseca
Emmanuel
E
Petroulakis
Xiaoshan
X
Wang
Ola
O
Larsson
Anand
A
Selvaraj
Yi
Y
Liu
Sara C
SC
Kozma
George
G
Thomas
Nahum
N
Sonenberg
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D049108:Cell Enlargement; D002460:Cell Line; D049109:Cell Proliferation; D048429:Cell Size; D002470:Cell Survival; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011506:Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus