The products of oncogenes have been categorized by structural/functional criteria and biological activity into four groups: 1. growth factors and their receptors; 2. signal transducing G proteins; 3. cytoplasmic serine/threonine protein kinases; and 4. nuclear factors involved in transcription. Recently, oncogenes have been described that do not fit into these traditional categories, such as the transnational initiation factor-4E (eIF-4E). eIF-4E has been shown to cause tumor growth in nude mice, and to induce DNA synthesis and morphological transformation after microinjection into NIH 3T3 cells. Tissue culture conditions that activate protein kinase C (PKC) activity, also result in the phosphorylation of eIF-4E. The DNA synthesis inducing activity of eIF-4E was shown to be enhanced 5-fold by co-injection of PKC and inhibited by co-injection of protein kinase A (PKA), or by activation of PKA activity with dibutyryl- cAMP (db-cAMP). The transforming activity of eIF-4E is inhibited with neutralizing anti-Ras monoclonal antibody or the dominant negative Ras mutant (Asn17). Cells transformed by overexpression of eIF-4E have increased amounts of activated Ras GTP complex. The growth of eIF-4E transformed cells in soft agar can be inhibited by addition of db-cAMP to the agar and the serum-induced phosphorylation of eIF-4E was inhibited by db-cAMP. These results demonstrate a direct biological connection between PKC and PKA and the activity of eIF-4E, and also demonstrate a requirement for G protein signal transduction in the activation of eIF-4E. Signals from the PKA-related pathways induce, while signals from the PKA-related pathways inhibit eIF-4E activity.
