Translational control by 80S formation and 60S availability: The central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis

Brina, Daniela; Grosso, Stefano; Miluzio, Annarita; Biffo, Stefano

doi:10.4161/cc.10.20.17796

Cited by 46 publications

(46 citation statements)

References 37 publications

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“…It is a highly coordinated process involving both transcriptional and post-transcriptional events that together control ribosomal protein synthesis. Ribosomal protein synthesis is increased in tumor cells [17], and it is crucial for tumor progression [18]. In fact, particularly aggressive phenotypes of cancer are associated with changes in nucleolar morphology including increased size, and require elevated rates of biosynthesis and higher levels of rRNA transcription [19]–[20].…”

Section: Introductionmentioning

confidence: 99%

The Transcription Factor EGR1 Localizes to the Nucleolus and Is Linked to Suppression of Ribosomal Precursor Synthesis

Ponti¹,

Bellenchi²,

Puca³

et al. 2014

PLoS ONE

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EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth. ARF is mainly localized to the periphery of nucleolus where is able to negatively regulate ribosome biogenesis. Since EGR1 colocalizes with ARF under IGF-1 stimulation we asked the question of whether EGR1 also relocate to the nucleolus to interact with ARF. Here we show that EGR1 colocalizes with nucleolar markers such as fibrillarin and B23 in the presence of ARF. Western analysis of nucleolar extracts from HeLa cells was used to confirm the presence of EGR1 in the nucleolus mainly as the 100 kDa sumoylated form. We also show that the level of the ribosomal RNA precursor 47S is inversely correlated to the level of EGR1 transcripts. The EGR1 iseffective to regulate the synthesis of the 47S rRNA precursor. Then we demonstrated that EGR1 binds to the Upstream Binding Factor (UBF) leading us to hypothesize that the regulating activity of EGR1 is mediated by its interaction within the transcriptional complex of RNA polymerase I. These results confirm the presence of EGR1 in the nucleolus and point to a role for EGR1 in the control of nucleolar metabolism.

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Section: Introductionmentioning

confidence: 99%

The Transcription Factor EGR1 Localizes to the Nucleolus and Is Linked to Suppression of Ribosomal Precursor Synthesis

Ponti¹,

Bellenchi²,

Puca³

et al. 2014

PLoS ONE

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“…It also has a role in the assembly of the 40S and 60S ribosomal subunits (Miluzio et al, 2009;Brina et al, 2011). eIF6 was first discovered in wheat germ as a ribosome disassociation factor that bound 60S ribosomes (Russell and Spremulli, 1978, 1979, 1980 and subsequently identified in yeast (Si et al, 1997) and mammals (Valenzuela et al, 1982;Raychaudhuri et al, 1984).…”

Section: Eif6 Groupmentioning

confidence: 99%

Mechanism of Cytoplasmic mRNA Translation

Browning

Bailey‐Serres

2015

The Arabidopsis Book

187

220

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Protein synthesis is a fundamental process in gene expression that depends upon the abundance and accessibility of the mRNA transcript as well as the activity of many protein and RNA-protein complexes. Here we focus on the intricate mechanics of mRNA translation in the cytoplasm of higher plants. This chapter includes an inventory of the plant translational apparatus and a detailed review of the translational processes of initiation, elongation, and termination. The majority of mechanistic studies of cytoplasmic translation have been carried out in yeast and mammalian systems. The factors and mechanisms of translation are for the most part conserved across eukaryotes; however, some distinctions are known to exist in plants. A comprehensive understanding of the complex translational apparatus and its regulation in plants is warranted, as the modulation of protein production is critical to development, environmental plasticity and biomass yield in diverse ecosystems and agricultural settings.

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“…98 A third case is represented by eIF6 and the ras-PKC cascade. 99 The role of eIF6 in tumor progression is remarkable. eIF6 is highly overexpressed in cancer cells 88,100 and is rate-limiting in fibroblast transformation.…”

Section: The Case For Rapamycin-insensitive Translationmentioning

confidence: 99%

Translation factors and ribosomal proteins control tumor onset and progression: how?

2013

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Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as 'ribosomopathies' that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting. The future is to design highly specific drugs targeting the translational apparatus.

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Translational control by 80S formation and 60S availability: The central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis

Cited by 46 publications

References 37 publications

The Transcription Factor EGR1 Localizes to the Nucleolus and Is Linked to Suppression of Ribosomal Precursor Synthesis

The Transcription Factor EGR1 Localizes to the Nucleolus and Is Linked to Suppression of Ribosomal Precursor Synthesis

Mechanism of Cytoplasmic mRNA Translation

Translation factors and ribosomal proteins control tumor onset and progression: how?

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