Translational control at the mRNA-binding step

Initiation of protein synthesis is catalyzed by initiation factors, which are in turn regulated is by their phosphorylation or by phosphorylation of modulating proteins. We are tracing signal transduction pathways from extracellular growth factors (e.g., insulin) which lead to phosphorylation of initiation factors. Insulin stimulates both general and "growth- regulated" mRNA translation by a pathway that involves insulin receptor, 1RS-1, and phosphatidylinositol-3-kinase. This pathway then bifurcates, one branch leading to phosphorylation of eIF4E and its binding protein, PHAS-I (a.k.a. 4E-BP) and the stimulation of "growth-regulated" protein synthesis, the other branch leading to enhanced activity of e]F2 or eIF2B and the stimulation of general protein synthesis. The intracellular concentration of initiation factors also regulates protein synthesis. eIF4G is specifically degraded by proteases encoded by picornaviruses but is synthesized by a cap-independent mechanism involving an internal ribosome entry site (1RES) on the eIF4G mRNA. We have found that this 1RES is considerably smaller than that of picornaviruses and initiates scanning down steam of an absolutely required polypyrimidine tract. This 1RES may permit eIF4G synthesis when cap-dependent translation is shut off. (Supported by Grants GM20818, DK43808, and DK38712 from the N1H and 3076 from the Council for Tobacco Research).