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Parsyan A.,McGill University | Hernandez G.,National Institute for Cancer INCan | Meterissian S.,McGill University
Cancer and Metastasis Reviews | Year: 2012

Colorectal cancers (CRC) are one of the most common causes of morbidity and mortality in high-income countries. Targeted screening programs have resulted in early treatment and a substantial decrease in mortality. However, treatment strategies for CRC still require improvement. Understanding the etiology and pathogenesis of CRC would provide tools for improving treatment of patients with this disease. It is only recently that deregulation of the protein synthesis apparatus has begun to gain attention as a major player in cancer development and progression. Among the numerous steps of protein synthesis, deregulation of the process of translation initiation appears to play a key role in cancer growth and proliferation. This manuscript discusses a fascinating and rapidly growing field exploring translation initiation as a fundamental component in CRC development and progression and summarizing CRC treatment perspectives based on agents targeting translation initiation. © 2012 Springer Science+Business Media, LLC.

Hernandez G.,National Institute for Cancer INCan | Proud C.G.,University of Southampton | Preiss T.,Australian National University | Parsyan A.,McGill University
Comparative and Functional Genomics | Year: 2012

Diversity is one of the most remarkable features of living organisms. Current assessments of eukaryote biodiversity reaches 1.5 million species, but the true figure could be several times that number. Diversity is ingrained in all stages and echelons of life, namely, the occupancy of ecological niches, behavioral patterns, body plans and organismal complexity, as well as metabolic needs and genetics. In this review, we will discuss that diversity also exists in a key biochemical process, translation, across eukaryotes. Translation is a fundamental process for all forms of life, and the basic components and mechanisms of translation in eukaryotes have been largely established upon the study of traditional, so-called model organisms. By using modern genome-wide, high-throughput technologies, recent studies of many nonmodel eukaryotes have unveiled a surprising diversity in the configuration of the translation apparatus across eukaryotes, showing that this apparatus is far from being evolutionarily static. For some of the components of this machinery, functional differences between different species have also been found. The recent research reviewed in this article highlights the molecular and functional diversification the translational machinery has undergone during eukaryotic evolution. A better understanding of all aspects of organismal diversity is key to a more profound knowledge of life. Copyright © 2012 Greco Hernndez et al.

Hernandez G.,McGill University | Hernandez G.,National Institute for Cancer INCan | Han H.,McGill University | Gandin V.,McGill University | And 7 more authors.
Development (Cambridge) | Year: 2012

Gene expression is translationally regulated during many cellular and developmental processes. Translation can be modulated by affecting the recruitment of mRNAs to the ribosome, which involves recognition of the 5_ cap structure by the cap-binding protein eIF4E. Drosophila has several genes encoding eIF4E-related proteins, but the biological role of most of them remains unknown. Here, we report that Drosophila eIF4E-3 is required specifically during spermatogenesis. Males lacking eIF4E-3 are sterile, showing defects in meiotic chromosome segregation, cytokinesis, nuclear shaping and individualization. We show that eIF4E-3 physically interacts with both eIF4G and eIF4G-2, the latter being a factor crucial for spermatocyte meiosis. In eIF4E-3 mutant testes, many proteins are present at different levels than in wild type, suggesting widespread effects on translation. Our results imply that eIF4E-3 forms specific eIF4F complexes that are essential for spermatogenesis. © 2012. Published by The Company of Biologists Ltd.

Ferrero P.V.,National University of La Plata | Ferrero P.V.,University of Buenos Aires | Layana C.,National University of La Plata | Layana C.,University of Buenos Aires | And 5 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2012

Eukaryotic translation initiation factor 4E (eIF4E) is required for cap-dependent initiation. In addition, eIF4E occurs in cytoplasmic foci such as processing bodies (PB) and stress granules (SG). We examined the role of key functional amino acid residues of eIF4E in the recruitment of this protein to cytoplasmic foci. We demonstrate that tryptophan residues required for mRNA cap recognition are not required for the recruitment of eIF4E to SG or PB. We show that a tryptophan residue required for protein-protein interactions is essential for the accumulation of eIF4E in granules. Moreover, we show, by the analysis of two Drosophila eIF4E isoforms, that the tryptophan residue is the common feature for eIF4E for the transfer of active mRNA from polysomes to other ribonucleoprotein particles in the cytoplasm. This residue resides in a putative interaction domain different than the eIF4E-BP domain. We conclude that protein-protein interactions rather than interactions with the mRNA are essential for the recruitment of eIF4E and for a putative nucleation function. © 2012 Elsevier B.V.

Tettweiler G.,McGill University | Kowanda M.,McGill University | Lasko P.,McGill University | Sonenberg N.,McGill University | Hernandez G.,National Institute for Cancer INCan
Comparative and Functional Genomics | Year: 2012

Insects are part of the earliest faunas that invaded terrestrial environments and are the first organisms that evolved controlled flight. Nowadays, insects are the most diverse animal group on the planet and comprise the majority of extant animal species described. Moreover, they have a huge impact in the biosphere as well as in all aspects of human life and economy; therefore understanding all aspects of insect biology is of great importance. In insects, as in all cells, translation is a fundamental process for gene expression. However, translation in insects has been mostly studied only in the model organism Drosophila melanogaster. We used all publicly available genomic sequences to investigate in insects the distribution of the genes encoding the cap-binding protein eIF4E, a protein that plays a crucial role in eukaryotic translation. We found that there is a diversity of multiple ortholog genes encoding eIF4E isoforms within the genus Drosophila. In striking contrast, insects outside this genus contain only a single eIF4E gene, related to D. melanogaster eIF4E-1. We also found that all insect species here analyzed contain only one Class II gene, termed 4E-HP. We discuss the possible evolutionary causes originating the multiplicity of eIF4E genes within the genus Drosophila. Copyright © 2012 Gritta Tettweiler et al.

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