Eukaryotic translation initiation factor 4E : its characterization as a proto-oncogene and mechanism of action

Eukaryotic cellular mRNAs have a 5$ sp prime$ cap structure (m7GpppX) that facilitates their binding to ribosomes and is required for efficient translation. An initiation factor, elF-4F, mediates the function of the cap and consists of three subunits. elF-4E, one of the subunits which binds the cap directly, is present in the cell in limiting amounts. We demonstrated that overexpression of elF-4E in NIH 3T3 and Rat 2 fibroblasts causes their tumorigenic transformation. We have also shown that elF-4E cooperates with an immortalizing, nuclear oncogene (ie. v-myc or E1A) to cause transformation of rat embryo fibroblasts. These findings categorize elF-4E as a proto-oncogene. The mode of transformation by elF-4E is similar to that of Ras-like proteins.To further elucidate the mechanism of elF-4E transformation we determined Ras activity in elF-4E transformed REFs. We detected an activation of Ras in eIF-4E overexpressing cells as compared to parental REFs. In addition, overexpression of GAP (GTPase activating-protein), a negative regulator of Ras, suppressed the transformation of REFs by elF-4E.In summary we have established an important link between Ras, which plays a key role in cellular signal transduction, and elF-4E which is a critical component of the translation machinery