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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    • "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.
    The Journal of Cell Biology 03/2015; 208(6):745-59. DOI:10.1083/jcb.201409056 · 9.83 Impact Factor
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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.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 12/2014; 1849(7). DOI:10.1016/j.bbagrm.2014.11.006 · 6.33 Impact Factor
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    • "Recently, Mendillo and colleagues (Mendillo et al., 2012) identified the genome-wide target sites of HSF1 in human breast cancer cell lines with different metastatic capacities, and also showed that HSF1-driven transcription is profoundly different in malignant cells compared with cells that are exposed to heat stress. Cancer cells display increased protein synthesis, which is supported by increased ribosomal biogenesis (Stumpf and Ruggero, 2011; White, 2005 and references therein). Intriguingly, a general block in translation was shown to almost fully abolish the binding of HSF1 to its target genes in cancer cells (Santagata et al., 2013). "
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    ABSTRACT: Heat shock factor 1 (HSF1) is an evolutionarily highly conserved transcription factor that coordinates stress-induced transcription and directs versatile physiological processes in eukaryotes. The central position of HSF1 in cellular homeostasis has been well demonstrated, mainly through its strong effect in transactivating genes that encode heat shock proteins (HSPs). However, recent genome-wide studies have revealed that HSF1 is capable of reprogramming transcription more extensively than previously assumed; it is also involved in a multitude of processes in stressed and non-stressed cells. Consequently, the importance of HSF1 in fundamental physiological events, including metabolism, gametogenesis and aging, has become apparent and its significance in pathologies, such as cancer progression, is now evident. In this Cell Science at a Glance article, we highlight recent advances in the HSF1 field, discuss the organismal control over HSF1, and present the processes that are mediated by HSF1 in the context of cell type, cell-cycle phase, physiological condition and received stimuli.
    Journal of Cell Science 01/2014; 127(Pt 2):261-6. DOI:10.1242/jcs.132605 · 5.43 Impact Factor
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