IRES elements: fine-tuning of gene expression at the translational level

Abstract

Some viral mRNAs contain internal ribosome entry sites (IRESs), which are cis elements that allow the binding of the translational apparatus directly within the mRNA. IRESs therefore offer an alternative to the general mechanism of the ribosome scanning from the 5′-end cap structure to the initiator codon that prevails for most cellular mRNAs. Interestingly, IRESs have also been identified in a few cellular messengers. Whereas viral IRESs provide the advantage of initiating translation in the case of uncapped mRNAs (e.g. picornaviruses mRNAs) or under conditions where the global host protein synthesis is inhibited (e.g. during infection), the biological function of cellular IRESs is still unclear. Recent ex vivo data have shown that certain cellular IRESs could mediate a cell-cycle-dependent translational control. In the July issue of the Journal of Cell Biology, Creancier and co-workers describe the first in vivo study of the activity of a mammalian cellular IRES, the human fibroblast growth factor 2 (FGF2) IRES (Ref. 1xFibroblast growth factor 2 internal ribosome entry site (IRES) activity ex vivo and in transgenic mice reveals a stringent tissue-specific regulation. Creancier, L. et al. J. Cell Biol. 2000; 150: 275–281Crossref | PubMed | Scopus (103)See all ReferencesRef. 1).The authors have created transgenic mice that express a dicistronic mRNA bearing two open reading frames (ORFs) encoding two distinct luciferases. In this standard assay, the upstream ORF is translated via the cap-dependent scanning mechanism, whereas translation of the second ORF is driven by the IRES located between them. By this method they could measure the IRES activity of the FGF2 mRNA specifically. Strikingly, they observed a stage- and tissue-specific modulation of the FGF2 IRES activity. It was high in the embryo (especially in the brain and the heart at E16) in comparison with the adult, in which this strong IRES activity appeared to be restricted mainly to the brain. This contrasted with the widespread strong activity of picornavirus IRESs. How does the tropism of FGF2 IRES activity fit with the broad expression of this growth factor all over the organism? The fact that FGF2 translation can be initiated via the IRES but also by a cap-dependent mechanism could explain such a discrepancy. Nevertheless, the poor IRES activity in organs that otherwise express FGF2 raises the question of the inducibility of IRESs. Indeed, stimulation of the FGF2 IRES could represent a means to adapt the level of FGF2 expression selectively in response to a given stimulus. This could involve potential as yet unidentified trans-acting factors that would be active in the adult brain while silent in other organs (in the steady state).The stringent in vivo regulation of the FGF2 IRES activity described in this paper emphasizes the role of translation in the control of gene expression, and the strategy applied here can be used for the in vivo study of other cellular IRESs. This could allow to address the question whether IRES elements coordinately regulate the translation of a subclass of mRNAs. Furthermore, the understanding of the molecular mechanisms underlying IRES regulation in vivo might lead to strategies designed to control the expression of endogenous factors artificially, as well as to target the expression of trans genes of interest. The animal model described here will represent an indispensable tool to validate such strategies.