GASTRIN INDUCES PHOSPHORYLATION OF EIF4E BINDING-PROTEIN-1 AND TRANSLATION INITIATION OF ORNITHINE DECARBOXYLASE MESSENGER-RNA

Gastrin via its G-protein coupled specific receptor induces transcript ion of c-fos and c-jun genes through a ras-MAPK pathway. Ornithine Dec arboxylase (ODC), a growth regulated proto-oncogene, was chosen to inv estigate gastrin effects on translation initiation of mRNAs exhibiting a 5'UnTranslated Region (5'UTR) responsible for translation repressio n in quiescent cells. In AR4-2J tumoral cells, we first demonstrated t hat gastrin increases ODC mRNA translation. Transient transfections wi th various CAT chimeric constructs suggested a direct involvement of t he 5'UTR in this observation. Translation of this group of mRNAs is en hanced by the availability of the cap-binding protein (eIF4E) that is increased after phosphorylation of its specific binding protein eIF4E- BP1, We found that AR4-2J cells overexpressed eIF4E protein which was not modulated by gastrin treatment. Rapamycin which inhibits 4E-BP1 ph osphorylation, completely prevents gastrin-mediated increase of ODC tr anslation indicating that 4E-BP1 could be involved in regulating ODC t ranslation. Implication of 4E-BP1 in mediating gastrin effects is corr oborated by the capacity of the ligand to affect 4E-BP1 phosphorylatio n, These results indicate that gastrin enhances ornithine decarboxylas e mRNA translation through a rapamycin sensitive pathway and provide t he first evidence in the control of 4E-BP1 phosphorylation after occup ancy of a G protein-coupled receptor.