Targeting protein synthesis in cancer cells

The G1 and S phases of the mitotic cell cycle normally insure that the parental cell attains a sufficient mass so as each daughter cell will have a size identical to that of the parental cell. This implies that before division cells must double their protein content, a process achieved through increase in protein synthesis. The most regulated step of protein synthesis is the initiation of mRNA translation into protein. Ribosome recruitment at the mRNA 5’ end is actually controlled by the mRNA 5’ cap binding protein eIF4E (eukaryotic translation initiation factor 4E) whose activity is inhibited by the hypophosphorylated forms of 4E-BPs (eIF4E-binding proteins 1 and 2) [1]. Upon mitogenic stimuli, mTOR phosphorylates 4E-BP1 and 4E-BP2 and the protein kinases S6K1 and S6K2 (S6Ks). 4E-BPs phosphorylation releases eIF4E which can interact with eIF4G itself bound to the RNA helicase eIF4A and to eIF3. Activated S6Ks phosphorylate eIF3 [2] and translation initiation is enhanced via eIF3-dependent recruitment of the 40S small ribosomal subunit and its subsequent joining with the large 60S subunit at the AUG initiator codon (Fig. 1). Consistent with a role of mTOR in G1-S transition,