Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies

Analysis of the recurrent genetic aberrations present in human tumors provides insight into how normal cells escape appropriate proliferation and survival cues. Commonly mutated genes encode proteins that monitor DNA damage (e.g., p53), proteins that regulate the cell cycle (such as Rb), and proteins that regulate signal transduction pathways (such as APC, PTEN and Ras). Analysis of the relevant targets and downstream events of these genes in normal and tumor cells will clearly highlight important pathways for tumorigenesis. However, more infrequent mutations are also informative in defining events critical for the process of tumorigenesis, and often delineate important pathways lying downstream of commonly mutated oncogenes and tumor suppressors. Together, these studies have led to the conclusion that deregulated protein synthesis plays an important role in human cancer. This review will discuss the evidence implicating mRNA translation as an important downstream consequence of signal transduction pathways initiated by mutated oncogenes and tumor suppressors, as well as additional genetic findings implicating the importance of global and specific translational control in human cancer. It will also discuss therapeutic strategies that take advantage of differences in translational regulation between normal and tumor cells.