The cancerous translation apparatus

School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158-3110, USA.
Current opinion in genetics & development (Impact Factor: 7.57). 05/2011; 21(4):474-83. DOI: 10.1016/j.gde.2011.03.007
Source: PubMed


Deregulations in translational control are critical features of cancer initiation and progression. Activation of key oncogenic pathways promotes rapid and dramatic translational reprogramming, not simply by increasing overall protein synthesis, but also by modulating specific mRNA networks that promote cellular transformation. Additionally, ribosomopathies caused by mutations in ribosome components alter translational regulation leading to specific pathological features, including cancer susceptibility. Exciting advances in our understanding of translational control in cancer have illuminated a striking specificity innate to the translational apparatus. Characterizing this specificity will provide novel insights into how cells normally utilize translational control to modulate gene expression, how it is deregulated in cancer, and how these processes can be targeted to develop new cancer therapies.

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    • "Using X-DC as a model, we showed that rRNA hypopseudouridylation decreases the affinity of ribosomes for at least two classes of RNA ligands, internal ribosomal entry signals (IRES) and tRNAs [30]. While this leads to decreased expression of IRES containing mRNAs (emerging as an important driver of cancer [31]), this biochemical defect also renders tRNAs more likely to slip at -1 PRF signals. The effects of X-DC associated mutations on -1 PRF and gene expression is currently a topic of intense research. "
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    ABSTRACT: Reading frame maintenance is a critical property of ribosomes. However, a number of genetic elements have been described that can induce ribosomes to shift on mRNAs, the most well understood of which are a class that directs ribosomal slippage by one base in 5' (-1) direction. This is referred to as programmed -1 ribosomal frameshifting (-1 PRF). Recently, a new -1 PRF promoting element was serendipitously discovered in a study examining the effects of stretches of adenosines in the coding sequences of mRNAs. Here, we discuss this finding, recent studies describing how -1 PRF is used to control gene expression in eukaryotes, and how -1 PRF is itself regulated. The implications of dysregulation of -1 PRF on human health are examined, as are possible new areas in which novel -1 PRF promoting elements might be discovered. Also watch the Video Abstract.
    Full-text · Article · Dec 2015 · BioEssays
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    • "As these cells rely exclusively in CK1 for growth and survival (Rosenberg et al., 2015), these findings indicate that the CK1- hLtv1 circuit is operational and essential for ribosome assembly in higher eukaryotes, which is consistent with previous findings that demonstrate a role for CK1/CK1 in 40S ribosome maturation (Zemp et al., 2014). Our findings are also consistent with previous observations that the ribosome assembly pathway is up-regulated in all cancers, which require marked increases in protein synthesis (Ruggero and Pandolfi, 2003; Stumpf and Ruggero, 2011). Finally, our findings validate the ribosome biogenesis machinery as an attractive and novel target for anticancer therapeutics. "
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    ABSTRACT: Casein kinase 1δ/ε (CK1δ/ε) and their yeast homologue Hrr25 are essential for cell growth. Further, CK1δ is overexpressed in several malignancies, and CK1δ inhibitors have shown promise in several preclinical animal studies. However, the substrates of Hrr25 and CK1δ/ε that are necessary for cell growth and survival are unknown. We show that Hrr25 is essential for ribosome assembly, where it phosphorylates the assembly factor Ltv1, which causes its release from nascent 40S subunits and allows subunit maturation. Hrr25 inactivation or expression of a nonphosphorylatable Ltv1 variant blocked Ltv1 release in vitro and in vivo, and prevented entry into the translation-like quality control cycle. Conversely, phosphomimetic Ltv1 variants rescued viability after Hrr25 depletion. Finally, Ltv1 knockdown in human breast cancer cells impaired apoptosis induced by CK1δ/ε inhibitors, establishing that the antiproliferative activity of these inhibitors is due, at least in part, to disruption of ribosome assembly. These findings validate the ribosome assembly pathway as a novel target for the development of anticancer therapeutics. © 2015 Ghalei et al.
    Full-text · Article · Mar 2015 · The Journal of Cell Biology
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    • "Many signaling pathways converge on components of the translational apparatus to regulate their function, particularly at the level of eukaryotic translation initiation factors (eIFs), such as eIF4E and eIF2α [2] [6]. Translational control is a crucial component of cancer development and progression, as it directs both global protein synthesis and the selective translation of mRNAs involved in tumor cell growth, survival and proliferation [7] [8] [9]. Consistent with this, many components of the translational machinery were reported to be amplified or overexpressed in human malignancies, including eIF4E, eIF4G, eIF4A and several eIF3 isoforms (Table 1) [9]. "
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    ABSTRACT: Messenger RNA (mRNA) translation is highly regulated in cells and plays an integral role in the overall process of gene expression. The initiation phase of translation is considered to be the most rate-limiting and is often targeted by oncogenic signaling pathways to promote global protein synthesis and the selective translation of tumor-promoting mRNAs. Translational control is a crucial component of cancer development as it allows cancer cells to adapt to the altered metabolism that is generally associated with the tumor state. The phosphoinositide 3-kinase (PI3K)/Akt and Ras/mitogen-activated protein kinase (MAPK) pathways are strongly implicated in cancer etiology, and they exert their biological effects by modulating both global and specific mRNA translation. In addition to having respective translational targets, these pathways also impinge on the mechanistic/mammalian target of rapamycin (mTOR), which acts as a critical signaling node linking nutrient sensing to the coordinated regulation of cellular metabolism. mTOR is best known as a central regulator of protein synthesis and has been implicated in an increasing number of pathological conditions, including cancer. In this article, we describe the current knowledge on the roles and regulation of mRNA translation by various oncogenic signaling pathways, as well as the relevance of these molecular mechanisms to human malignancies. This article is part of a Special Issue entitled: Translation and Cancer. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Dec 2014 · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
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