Translational upregulation of yes accompanies eIF4E-mediated oncogenic transformation

Overexpression of the translation initiation factor eIF4E results in transformation of normal fibroblasts as a single-hit oncogene. This implies that eIF4E must affect several pathways leading to transformation. The oncogenic potential of eIF4E is probably realized by elevating the translational efficiency of some oncogene and growth-promotion transcripts that are normally repressed by their 5'UTR (untranslated region). To address this possibility, we have cloned mRNAs whose polysomal representation increases upon overexpression of eIF4E. Among these mRNAs, we now report the isolation of a clone corresponding to the src-like kinase yes. The yes mRNA contains a long 5'UTR with characteristic features of a typical translationally repressed transcript. This was confirmed by analysis of the distribution of yes mRNA after sedimentation in sucrose gradients. Increased utilization of yes mRNA resulted in elevated expression of the protein product in cells transformed with eIF4E, and suggested that overexpression of Yes could contribute to eIF4E-mediated transformation. To test this, we monitored the malignant properties of MM3MG-4E cells after treatment with PP2, a specific inhibitor of src kinases. Growth in soft agar and saturation densities were significantly reduced after treatment with PP2, but treatment of mice harboring MM3MG-4E tumors with PP2 did not affect tumor growth. However, transformation of yes-null fibroblasts by eIF4E was significantly impaired.