Cell cycle progression and proliferation despite 4BP-1 dephosphorylation

Proliferation and cell cycle progression in response to growth factors requ ire de novo protein synthesis. It has been proposed that binding of the euk aryotic 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 t he mRNA. The signal for translation initiation is thought to involve phosph orylation of 4BP-1, which causes it to dissociate from eIF-4E and allows eI F-4G to localize to the 5' cap. It has been suggested that the ability of t he macrolide antibiotic rapamycin to inhibit 4BP-1 phosphorylation is respo nsible for the potent antiproliferative property of this drug. We now show that rapamycin-resistant cells exhibited normal proliferation despite depho sphorylation of 4BP-1 that allows it to bind to eIF-4E. Moreover, despite r apamycin-induced dephosphorylation of 4BP-1, eIF-4E-eIF-4G complexes (eIF-4 F) 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 e IF-4E inactivation and does not explain the antiproliferative property of r apamycin.