DeBenedetti 9513756 Our laboratory studies the mechanism of translation initiation and the role of eIF-4 factors (particularly 4E) in this process. The premise of this proposal emerged from studies of two important growth control genes: c-myc and FGF-2, in which translation can begin from either the first AUG, or from CUG codons located upstream and in-frame with the AUG codon. The resulting amino-terminal extension alters the properties of these regulatory proteins and particularly their intracellular distribution. For instance, FGF-2 is a powerful cytokine, but it is not normally secreted; we found that the CUG1-initiated isoform is exported, making it a more potent mitogen. Elevating the level of eIF-4E results in overexpression of c-myc and FGF-2, but it also enhances synthesis of the larger, CUG-initiated isoforms. A few additional important mRNAs have similar translation features (Oskar, L-myc, lyl-1, pim-1, int-2 and Mod5). We anticipate that this work will: i) elucidate the role of eIF-4E in enhancing translation of weak mRNAs; ii) improve our understanding of the synthesis of the larger forms of c-Myc and FGF-2; iii) improve our understanding of the mechanism of translation initiation and selection of start codon(s); and iv) elucidate the mechanism of recognition of translation start codons. %%% The mechanism of translation initiation and the role of certain factors in this process are not well understood. It is proposed to study two important growth control genes: c-myc and FGF-2, in which translation can begin from either the first initiation codon (AUG), or from other (CUG) codons located upstream and in-frame with the AUG codon. The resulting amino-terminal extension alters the properties of these regulatory proteins and particularly their intracellular distribution. For instance, FGF-2 is a powerful cytokine, but it is not normally secreted. We found that the CUG1-initiated isoform is exported, making it a more potent mitogen. Elevating the level of the transcr iption factor eIF-4E results in overexpression of c-myc and FGF-2, but it also enhances synthesis of the larger, CUG-initiated isoforms. We anticipate that this work will: i) elucidate the role of eIF-4E in enhancing translation of weak mRNAs; ii) improve our understanding of the synthesis of the larger forms of c-Myc and FGF-2; iii) improve our understanding of the mechanism of translation initiation and selection of start codon(s); and iv) elucidate the mechanism of recognition of translation start codons. ***
