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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    • "Thus, the UPR can be a double-edged sword during tumorigenesis. cells are often characterized by increased rates of protein synthesis and also face conditions of glucose and oxygen deprivation in the tumor microenvironment [13] [14]. Adaptation to such adverse conditions requires an ER with enhanced folding capacity achieved by increased presence of chaperones and folding enzymes. "
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    ABSTRACT: A variety of cell intrinsic or extrinsic stresses evoke perturbations in the folding environment of the endoplasmic reticulum (ER), collectively known as ER stress. Adaptation to stress and re-establishment of ER homeostasis is achieved by activation of an integrated signal transduction pathway called the unfolded protein response (UPR). Both ER stress and UPR activation have been implicated in a variety of human cancers. Although at early stages, or physiological conditions of ER stress, the UPR generally promotes survival, when the stress becomes more stringent or prolonged, its role can switch to a pro-cell death one. Here, we discuss historical and recent evidence supporting an involvement of the UPR in malignancy, describe the main mechanisms by which how tumor cells overcome ER stress to promote their survival, tumor progression and metastasis and discuss the current state of efforts to develop therapeutic approaches of targeting the UPR. Copyright © 2015. Published by Elsevier Ltd.
    Seminars in Cancer Biology 04/2015; 33. DOI:10.1016/j.semcancer.2015.04.002 · 9.33 Impact Factor
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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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    ABSTRACT: Abstract The conventional paradigm of translation initiation in eukaryotes states that the cap-binding protein complex eIF4F (consisting of eIF4E, eIF4G and eIF4A) plays a central role in the recruitment of capped mRNAs to ribosomes. However, a growing body of evidence indicates that this paradigm should be revised. This review summarizes the data which have been mostly accumulated in a post-genomic era owing to revolutionary techniques of transcriptome-wide analysis. Unexpectedly, these techniques have uncovered remarkable diversity in the recruitment of cellular mRNAs to eukaryotic ribosomes. These data enable a preliminary classification of mRNAs into several groups based on their requirement for particular components of eIF4F. They challenge the widely accepted concept which relates eIF4E-dependence to the extent of secondary structure in the 5' untranslated regions of mRNAs. Moreover, some mRNA species presumably recruit ribosomes to their 5' ends without the involvement of either the 5' m(7)G-cap or eIF4F but instead utilize eIF4G or eIF4G-like auxiliary factors. The long-standing concept of internal ribosome entry site (IRES)-elements in cellular mRNAs is also discussed.
    Critical Reviews in Biochemistry and Molecular Biology 02/2014; 49(2). DOI:10.3109/10409238.2014.887051 · 7.71 Impact Factor
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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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    ABSTRACT: Tumour mutations corrupt cellular pathways, and accumulate to disrupt, dysregulate, and ultimately avoid mechanisms of cellular control. Yet the very changes that tumour cells undergo to secure their own growth success also render them susceptible to viral infection. Enhanced availability of surface receptors, disruption of antiviral sensing, elevated metabolic activity, disengagement of cell cycle controls, hyperactivation of mitogenic pathways, and apoptotic avoidance all render the malignant cell environment highly supportive to viral replication. The therapeutic use of oncolytic viruses (OVs) with a natural tropism for infecting and subsequently lysing tumour cells is a rapidly progressing area of cancer research. While many OVs exhibit an inherent degree of tropism for transformed cells, this can be further promoted through pharmacological interventions and/or the introduction of viral mutations that generate recombinant oncolytic viruses adapted to successfully replicate only in a malignant cellular environment. Such adaptations that augment OV tumour selectivity are already improving the therapeutic outlook for cancer, and there remains tremendous untapped potential for further innovation.
    PLoS Pathogens 01/2014; 10(1):e1003836. DOI:10.1371/journal.ppat.1003836 · 7.56 Impact Factor
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