8 mRNA 5′ Cap-binding Protein elF4E and Control of Cell Growth

Modulation of translation rates accompanies major biological processes including proliferation, differentiation, and development. A general increase in the rate of translation is required for both entry into and transit through the cell cycle (Brooks 1977). Reentry of cells from the resting state, G 0 , into the cell cycle is effected by several extracellular stimuli. These stimuli include growth factors and hormones that activate multiple signaling pathways that enhance transcription and translation rates and stimulate cell proliferation. Several major signal transduction pathways have been elucidated, and many of the components that link extracellular receptors to the translational and transcriptional machineries have been characterized. Many of these components function in phosphorylation cascades. Translation rates increase in response to treatment with growth factors, cytokines, hormones, and mitogens (for reviews, see Rhoads 1991; Frederickson and Sonenberg 1993; Sonenberg 1993; Morris 1995). The list of translation components, whose involvement in control of cell growth has been documented, is large and expanding. These include the translation initiation factors (eIF, for eukaryotic initiation factor) eIF2, eIF2B, eIF4E, possibly eIF4B, eIF4G, and eIF3; the elongation factors eEF1 and eEF2; and the ribosomal protein S6. Evidence also exists in yeast that translation initiation controls G 1 progression, and mutations in several eIFs cause an early G 1 arrest (Brenner et al. 1988; Hartwell and McLaughlin 1968). The large number of eIFs implicated in control of cell growth indicates that the mechanisms by which translation rates modulate cell growth are highly complex and integrate the activities of numerous elements. Most of the control...