Abstract
Overexpression of the translation initiation factor eIF4E 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 eIF4E to form initiation complexes by binding to eIF4G. The availability of eIF4E is blocked through the binding of members of a family of eIF4E-binding proteins (4E-BPs) [2,3]. Indeed, cell transformation caused by the overexpression of eIF4E can be reversed by the overexpression of 4E-BPs [4-83]. To study the role of eIF4E 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 eIF4E-binding peptides into MRC5 cells led to rapid, dose-dependent call death, with characteristics of apoptosis. Single alanine substitutions at key positions in the peptides impair their binding to eIF4E and markedly reduce their ability to induce apoptosis. A triple alanine substitution, which abolishes binding to eIF4E, renders the peptide unable to induce apoptosis. Our data provide strong evidence that the peptides induce apoptosis through binding to eIF4E. 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 eIF4E has a direct role in controlling cell survival that is not linked to its known role in mRNA translation.
| Original language | English |
|---|---|
| Pages (from-to) | 793-796 |
| Number of pages | 4 |
| Journal | Current Biology |
| Volume | 10 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - 1 Jun 2000 |
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Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E. / Herbert, Terence P. (Lead / Corresponding author); Fåhraeus, Robin; Prescott, Alan; Lane, David P.; Proud, Chris G.
In: Current Biology, Vol. 10, No. 13, 01.06.2000, p. 793-796.Research output: Contribution to journal › Article
TY - JOUR
T1 - Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E
AU - Herbert, Terence P.
AU - Fåhraeus, Robin
AU - Prescott, Alan
AU - Lane, David P.
AU - Proud, Chris G.
PY - 2000/6/1
Y1 - 2000/6/1
N2 - Overexpression of the translation initiation factor eIF4E 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 eIF4E to form initiation complexes by binding to eIF4G. The availability of eIF4E is blocked through the binding of members of a family of eIF4E-binding proteins (4E-BPs) [2,3]. Indeed, cell transformation caused by the overexpression of eIF4E can be reversed by the overexpression of 4E-BPs [4-83]. To study the role of eIF4E 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 eIF4E-binding peptides into MRC5 cells led to rapid, dose-dependent call death, with characteristics of apoptosis. Single alanine substitutions at key positions in the peptides impair their binding to eIF4E and markedly reduce their ability to induce apoptosis. A triple alanine substitution, which abolishes binding to eIF4E, renders the peptide unable to induce apoptosis. Our data provide strong evidence that the peptides induce apoptosis through binding to eIF4E. 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 eIF4E has a direct role in controlling cell survival that is not linked to its known role in mRNA translation.
AB - Overexpression of the translation initiation factor eIF4E 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 eIF4E to form initiation complexes by binding to eIF4G. The availability of eIF4E is blocked through the binding of members of a family of eIF4E-binding proteins (4E-BPs) [2,3]. Indeed, cell transformation caused by the overexpression of eIF4E can be reversed by the overexpression of 4E-BPs [4-83]. To study the role of eIF4E 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 eIF4E-binding peptides into MRC5 cells led to rapid, dose-dependent call death, with characteristics of apoptosis. Single alanine substitutions at key positions in the peptides impair their binding to eIF4E and markedly reduce their ability to induce apoptosis. A triple alanine substitution, which abolishes binding to eIF4E, renders the peptide unable to induce apoptosis. Our data provide strong evidence that the peptides induce apoptosis through binding to eIF4E. 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 eIF4E has a direct role in controlling cell survival that is not linked to its known role in mRNA translation.
UR - http://www.scopus.com/inward/record.url?scp=0343167422&partnerID=8YFLogxK
U2 - 10.1016/S0960-9822(00)00567-4
DO - 10.1016/S0960-9822(00)00567-4
M3 - Article
C2 - 10898981
AN - SCOPUS:0343167422
VL - 10
SP - 793
EP - 796
JO - Current Biology
JF - Current Biology
SN - 0960-9822
IS - 13
ER -