Background: mTORC1 plays an important role in the regulation of TOP mRNA translation. Results: LARP1 is a target of mTORC1 that associates with TOP mRNAs via their 5ЈTOP motif to repress their translation. Conclusion: LARP1 represses TOP mRNA translation downstream of mTORC1. Significance: We elucidate an important novel signaling pathway downstream of mTORC1 that controls the production of ribosomes and translation factors in eukaryotic cells.
The Drosophila genome-sequencing project has revealed a total of seven genes encoding eight eukaryotic initiation factor 4E (eIF4E) isoforms. Four of them (eIF4E-1,2, eIF4E-3, eIF4E-4 and eIF4E-5) share exon/intron structure in their carboxy-terminal part and form a cluster in the genome. All eIF4E isoforms bind to the cap (m7GpppN) structure. All of them, except eIF4E-6 and eIF4E-8 were able to interact with Drosophila eIF4G or eIF4E-binding protein (4E-BP). eIF4E-1, eIF4E-2, eIF4E-3, eIF4E-4 and eIF4E-7 rescued a yeast eIF4E-deficient mutant in vivo. Only eIF4E-1 mRNAs and, at a significantly lower level, eIF4E3 and eIF4E-8 are expressed in embryos and throughout the life cycle of the fly. The transcripts of the remaining isoforms were detected from the third instar larvae onwards. This indicates the cap-binding activity relies mostly on eIF4E-1 during embryogenesis. This agrees with the proteomic analysis of the eIF4F complex purified from embryos and with the rescue of l(3)67Af, an embryonic lethal mutant for the eIF4E-1,2 gene, by transgenic expression of eIF4E-1. Overexpression of eIF4E-1 in wild-type embryos and eye imaginal discs results in phenotypic defects in a dose-dependent manner.
Protein synthesis in eukaryotic cells is fundamental for gene expression. This process involves the binding of an mRNA molecule to the small ribosomal subunit in a group of reactions catalyzed by eukaryotic translation initiation factors (eIF) eIF4. To date, the role of each of the four eIF4, i.e. eIF4E, eIF4G, eIF4A and eIF4B, is well established. However, with the advent of genome-wide sequencing projects of various organisms, families of genes for each translation initiation factor have been identified. Intriguingly, recent studies have now established that certain eIF4 proteins can promote or inhibit translation of specific mRNAs, and also that some of them are active in processes other than translation. In addition, there is evidence of tissue- and developmental-stage-specific expression for some of these proteins. These new findings point to an additional level of complexity in the translation initiation process. In this review, we analyze the latest advances concerning the functionality of members of the eIF4 families in eukaryotic organisms and discuss the implications of this in the context of our current understanding of regulation of the translation initiation process.
Translation is a sensitive regulatory step during cellular stress and the apoptosis response. Under such conditions, cap-dependent translation is reduced and internal ribosome entry site (IRES)-dependent translation plays a major role. However, many aspects of how mRNAs are translated under stress remain to be elucidated. Here we report that reaper mRNA, a pro-apoptotic gene from Drosophila melanogaster, is translated in a cap-independent manner. In Drosophila mutant embryos devoid of the eukaryotic initiation factor 4E (eIF4E), reaper transcription is induced and apoptosis proceeds. In vitro translation experiments using wild-type and eIF4E mutant embryonic extracts show that reporter mRNA bearing reaper 5 untranslated region (UTR) is effectively translated in a cap-independent manner. The 5UTR of reaper exhibits a high degree of similarity with that of Drosophila heat shock protein 70 mRNA, and both display IRES activity. Studies of mRNA association to polysomes in embryos indicate that both reaper and heat shock protein 70 mRNAs are recruited to polysomes under apoptosis or thermal stress. Our data suggest that heat shock protein 70 and reaper, two antagonizing factors in apoptosis, use a similar mechanism for protein synthesis.
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