Translational homeostasis: Eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities

Eukaryotic translation initiation factor 4E (eIF4E) is the mRNA 5' cap bind ing protein, which plays an important role in the control of translation. T he activity of eIF4E is regulated by a Family of repressor proteins, the 4E -binding proteins (4E-BPs), whose binding to eIF4E is determined by their p hosphorylation state. When hyperphosphorylated, 4E-BPs do not bind to eIF4E . Phosphorylation of the 4E-BPs is effected by the phosphatidylinositol (PI ) 3-kinase signal transduction pathway and is inhibited by rapamycin throug h its binding to FRAP/mTOR (FK506 binding protein-rapamycin-associated prot ein or mammalian target of rapamycin). Phosphorylation of 4E-BPs can also b e induced by protein synthesis inhibitors. These observations led to the pr oposal that FRAP/mTOR functions as a "sensor" of the translational apparatu s (E. J. Brown and S. L. Schreiber, Cell 86:517-520, 1996), To test this mo del, we have employed the tetracycline-inducible system to increase eIF4E e xpression. Removal of tetracycline induced eIF4E expression up to fivefold over endogenous levels. Strikingly, upon induction of eIF4E, 4E-BP1 became dephosphorylated and the extent of dephosphorylation was proportional to th e expression level of eIF4E. Dephosphorylation of p70(S6k) also occurred up on eIF4E induction. In contrast, the phosphorylation of Akt, an upstream ef fector of both p70(S6k) and 4E-BP phosphorylation, was not affected by eIF4 E induction. We conclude that eIF4E engenders a negative feedback loop that targets a component of the PI 3-kinase signalling pathway which lies downs tream of PI 3-kinase.