eIF4E activity is regulated at multiple levels

A key regulatory step in translation is initiation, or the recruitment of t he translational machinery to the 5 ' end of mRNA. The 5 ' terminus of most mRNAs is demarcated by a mTiGpppN cap (where m is a methyl group, and N is anp nucleotide). The m7 cap is essential for the translation of most mRNAs , as it directs the translational machinery to the 5 ' end of the mRNA via its interaction with the cap binding protein, the eukaryotic translation in itiation factor 4E (eIF4E). eIF4E is the limiting initiation factor in most cells. Thus, eIF4E activity plays a principal role in determining global t ranslation rates. Consistent with this role, eIF4E is required for cell cyc le progression, exhibits anti-apoptotic activity, and, when overexpressed, transforms cells. This review focuses upon the various mechanisms utilized in the regulation of eIF4E activity. (1) eIF4E is regulated transcriptionally; it is one of t he few identified transcriptional targets of c-myc. (2) eIF4E is phosphoryl ated following activation of the MNK1 kinase, a substrate of the ERK and p3 8 MAPKs. The recent determination of the three-dimensional structure of eIF 4E bound to a m7 cap analog has provided insight into the mechanisms involv ed in the regulation of the eIF4E-cap and eIF4E-mRNA interactions. As sugge sted by the crystal structure, phosphorylation of eIF4E may enhance its aff inity for mRNA. (3) eIF4E is also regulated through binding to a family of translational repressor proteins. Interaction with the 4E-BPs prevents the incorporation of eIF4E into an active translation initiation complex, and t hus, inhibits cap-dependent translation. This inhibitory interaction is rel ieved following phosphorylation of the 4E-BPs by a PI3K-dependent pathway, involving signalling by the anti-apoptotic kinase Akt/PKB, as well as FRAP/ mTOR. (C) 1999 Elsevier Science Ltd. All rights reserved.