Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
RevieweIF6 anti-association activity is required for ribosome biogenesis, translational control and tumor progression☆
Introduction
eIF6 (eukaryotic Inititiation Factor 6) activity was first described by the pioneering works of the laboratories of Spremulli [57] and Maitra [70] that described a ribosomal antiassociation activity. Cloning of the gene occurred only in the late '90s [6], [64]. From that moment, a limited number of thorough investigations unveiled the peculiar properties of this protein, which makes it a master regulator of translation and tumor progression, in vivo.
Section snippets
eIF6 structure and expression: the basics
eIF6 is an evolutionarily conserved protein of 245 amino acids, 77% identical between yeasts and humans [6]. Truncated isoforms of eIF6 are present in mammalian nucleotide databases, but they have never been observed at the protein level (Biffo, unpublished observations). Despite of conservation, the primary sequence of eIF6 has no homologs or conserved motifs. No evidence for gene duplication exists, suggesting a strong pressure for tight gene dosage, an expectation confirmed by studies in
eIF6 function in ribosome biogenesis
eIF6 localizes both in the nucleolus, where it is enriched in the perinucleolar region, and in the cytoplasm [32], [59]. The presence of eIF6 in the nucleolus supports a role in ribosome biogenesis. Ribosome biogenesis is a conserved process in eukaryotes [19], [33]. In S. cerevisiae, the pathway begins with transcription of the 35S and 5S ribosomal RNA (rRNA) precursors by RNA polymerases I and III, respectively. The association of ribosomal proteins and pre-ribosomal factors with nascent
eIF6 antiassociation activity in translation in normal tissues
eIF6 inhibits the association of 40S and 60S ribosomal subunits into 80S, in vitro [57], [70]. Low concentrations of eIF6 have a slight stimulatory effect on translation, in vitro [57], [70], whereas high concentrations of either eIF6 [11] or aIF6, the Archibacteria homolog [5], inhibit translation. These results suggest that the antiassociation activity of eIF6 needs to be regulated by cellular factors in order to be functional and to avoid translation inhibition. However, it is evident that
Model of eIF6 release from the 60S
Since the binding of eIF6 to the large 60S subunit is mutually exclusive with 40S joining and translation, a release mechanism leading to its dissociation must exists. Two models have been proposed [39], but further work is needed because the picture is still unclear. The first model sustains that the release of eIF6 from 60S is mediated by the SBDS-efl1 complex. Efl1 is a cytoplasmic GTPase homologous to the bacterial ribosomal elongation factor EF-G/EF-2 [61]. The deletion of Efl1 results in
eIF6 in cancer
Increased rates of protein synthesis have been associated with cell growth and transformation [56], but alterations in the ribosomal machinery have been considered for a long time only a by-product of transformation and tumor growth. This view was challenged in recent years by genetic evidence demonstrating that ribosomal alterations modulate tumorigenesis [34], [66]. Enlargement of eIF6 containing nucleoli is a feature of aggressive colorectal tumors [59]. eIF6 is rate limiting for
Shwachman–Bodian–Diamond (SDS) syndrome
The insufficiency of either ribosomal proteins or transacting factors in ribosome biogenesis can result in increased susceptibility to cancer, despite a general reduction in growth capability. This is evident, for instance, in Shwachman–Diamond syndrome (SDS) where neutropenia, exocrine pancreas dysfunction and metaphyseal chondrodysplasia are accompanied by an increased risk of developing myelodysplastic syndrome and acute myeloid leukemia [42]. SDS is an autosomal recessive disorder caused by
Concluding remarks and controversies
Based on our knowledge, we conclude that the anti-association activity of eIF6 acts at two different levels: (1) biogenesis of 60S subunit and export from the nucleus to the cytoplasm and (2) translational control. How the anti-association/dissociation activity functions at the level of translation initiation is still obscure. The specific effects of eIF6 inhibition suggest that somehow 60S availability affects the specific translation of mRNAs. Perhaps reinitiation at uORFs sequences or
Acknowledgements
Work in our laboratory has been generously funded by AIRC IG2011, AICR 13-0045, Fondazione Buzzi UNICEM and TELETHON GGP10012.
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This article is part of a Special Issue entitled: Translation and Cancer.