Abstract
The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Androstadienes / pharmacology
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Animals
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Carrier Proteins / pharmacology
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Cell Cycle Proteins
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Cell Line
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DNA-Binding Proteins / pharmacology
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Eukaryotic Initiation Factor-4E
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G1 Phase
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Heat-Shock Proteins / pharmacology
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Humans
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Insulin / pharmacology
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Intracellular Signaling Peptides and Proteins
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Peptide Initiation Factors / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Polyenes / pharmacology*
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Protein Kinases*
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Rats
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Recombinant Proteins / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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Sirolimus
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TOR Serine-Threonine Kinases
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Tacrolimus Binding Proteins
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Transfection
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Tumor Cells, Cultured
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Wortmannin
Substances
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Adaptor Proteins, Signal Transducing
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Androstadienes
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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EIF4EBP1 protein, human
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Eif4ebp1 protein, rat
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Eukaryotic Initiation Factor-4E
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Heat-Shock Proteins
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Insulin
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Intracellular Signaling Peptides and Proteins
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Peptide Initiation Factors
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Phosphoproteins
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Polyenes
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Recombinant Proteins
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Repressor Proteins
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Protein Kinases
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Phosphotransferases (Alcohol Group Acceptor)
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MTOR protein, human
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mTOR protein, rat
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TOR Serine-Threonine Kinases
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Tacrolimus Binding Proteins
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Sirolimus
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Wortmannin