Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E

Overexpression of the translation initiation factor elF4E leads to cell transformation and occurs in a number of human cancers [1]. mRNA translation and cell growth can be regulated through the availability of elF4E to form initiation complexes by binding to elF4G. The availability of elF4E Is blocked through the binding of members of a family of elF4E-binding proteins (4E-BPs) [2,3]. Indeed, cell transformation caused by the overexpression of elF4E can be reversed by the overexpression of 4E-BPs [4-8]. To study the role of elF4E in cell transformation, we developed a series of peptides based on the conserved elF4E-binding motifs in 4E-BPs and elF4G [9] linked to the penetratin peptide-carrier sequence, which mediates the rapid transport of peptides across cell membranes. surprisingly, introduction of these elF4E-binding peptides into MRC5 cells led to rapid, dose dependent cell death, with characteristics of apoptosis. Single alanine substitutions at key positions in the peptides impair their binding to elF4E and markedly reduce their ability to induce apoptosis. A triple alanine substitution, which abolishes binding to elF4E, renders the peptide unable to induce apoptosis. Our data provide strong evidence that the peptides induce apoptosis through binding to elF4E. They do not induce apoptosis through inhibition of protein synthesis, as chemical inhibitors of translation did not induce apoptosis or affect peptide-induced cell death. Thus these new data indicate that elF4E has a direct role in controlling cell survival that is not linked to its known role in mRNA translation. (C) 2000 Elsevier Science Ltd. All rights reserved.