Cell cycle progression and proliferation despite 4BP-1 dephosphorylation.
Proliferation and cell cycle progression in response to growth factors require de novo protein synthesis. It has been proposed that binding of the eukaryotic translation initiation factor 4E (eIF-4E) to the inhibitory protein 4BP-1 blocks translation by preventing access of eIF-4G to the 5' cap of the mRNA. The signal for translation initiation is thought to involve phosphorylation of 4BP-1, which causes it to dissociate from eIF-4E and allows eIF-4G to localize to the 5' cap. It has been suggested that the ability of the macrolide antibiotic rapamycin to inhibit 4BP-1 phosphorylation is responsible for the potent antiproliferative property of this drug. We now show that rapamycin-resistant cells exhibited normal proliferation despite dephosphorylation of 4BP-1 that allows it to bind to eIF-4E. Moreover, despite rapamycin-induced dephosphorylation of 4BP-1, eIF-4E-eIF-4G complexes (eIF-4F) were still detected. In contrast, amino acid withdrawal, which caused a similar degree of 4BP-1 dephosphorylation, resulted in dissociation of the eIF-4E-eIF-4G complex. Thus, 4BP-1 dephosphorylation is not equivalent to eIF-4E inactivation and does not explain the antiproliferative property of rapamycin.
Marx
S O
SO
Molecular Cardiology Program, Divisions of Cardiology and Circulatory Physiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Marks
A R
AR
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D006224:Cricetinae; D004351:Drug Resistance; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D046911:Macromolecular Substances; D051379:Mice; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D010448:Peptide Initiation Factors / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D046911:Macromolecular Substances; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D020123:Sirolimus