Translational Control in Cancer Etiology

Helen Diller Cancer Center, School of Medicine, University of California, San Francisco, California 94158.
Cold Spring Harbor perspectives in biology (Impact Factor: 8.68). 07/2012; 5(2). DOI: 10.1101/cshperspect.a012336
Source: PubMed


The link between perturbations in translational control and cancer etiology is becoming a primary focus in cancer research. It has now been established that genetic alterations in several components of the translational apparatus underlie spontaneous cancers as well as an entire class of inherited syndromes known as "ribosomopathies" associated with increased cancer susceptibility. These discoveries have illuminated the importance of deregulations in translational control to very specific cellular processes that contribute to cancer etiology. In addition, a growing body of evidence supports the view that deregulation of translational control is a common mechanism by which diverse oncogenic pathways promote cellular transformation and tumor development. Indeed, activation of these key oncogenic pathways induces rapid and dramatic translational reprogramming both by increasing overall protein synthesis and by modulating specific mRNA networks. These translational changes promote cellular transformation, impacting almost every phase of tumor development. This paradigm represents a new frontier in the multihit model of cancer formation and offers significant promise for innovative cancer therapies. Current research, in conjunction with cutting edge technologies, will further enable us to explore novel mechanisms of translational control, functionally identify translationally controlled mRNA groups, and unravel their impact on cellular transformation and tumorigenesis.

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    • "Nevertheless, there is a general agreement that the eIF4E dependence varies among individual mRNAs, as some mRNAs still continue to bind ribosomes under stress conditions when eIF4E1 is inactivated by 4E-BPs and the scaffold factor eIF4G is cleaved by virus proteases or caspases (Figure 1A). Such stress-resistant cellular mRNAs are believed to harbor IRES-elements within their 5 0 UTRs (for review, see Ruggero, 2013). "
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    • "While enhancing metabolic activity, suppressing antiviral signaling, and increasing nucleotide levels are all necessary and potentially rate-limiting steps for optimizing cancer growth or viral infection, the translation of proteins ultimately represents the final hurdle that ensures either cellular growth/division or the production of viral particle components. Dysregulation of translational control is one of the key events that promotes cellular transformation, and enhanced ribosome biogenesis, elevated levels of initiation factors, and changes in transcriptional repressors are found in a broad spectrum of cancers [69]. Since all eukaryotic viruses are fully dependent on host cell translational machinery to synthesize viral proteins, virus-host cell interactions that regulate translation, both globally and for specific mRNAs, contribute to the oncotropism of certain OVs (Figure 2). "
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