eIF4E is a central node of an RNA regulon that governs cellular proliferation

Abstract

This study demonstrates that the eukaryotic translation initiation factor eIF4E is a critical node in an RNA regulon that impacts nearly every stage of cell cycle progression. Specifically, eIF4E coordinately promotes the messenger RNA (mRNA) export of several genes involved in the cell cycle. A common feature of these mRNAs is a structurally conserved, ∼50-nucleotide element in the 3′ untranslated region denoted as an eIF4E sensitivity element. This element is sufficient for localization of capped mRNAs to eIF4E nuclear bodies, formation of eIF4E-specific ribonucleoproteins in the nucleus, and eIF4E-dependent mRNA export. The roles of eIF4E in translation and mRNA export are distinct, as they rely on different mRNA elements. Furthermore, eIF4E-dependent mRNA export is independent of ongoing RNA or protein synthesis. Unlike the NXF1-mediated export of bulk mRNAs, eIF4E-dependent mRNA export is CRM1 dependent. Finally, the growth-suppressive promyelocytic leukemia protein (PML) inhibits this RNA regulon. These data provide novel perspectives into the proliferative and oncogenic properties of eIF4E.

Controlling Gene Expression through RNA Regulons: The Role of the Eukaryotic Translation Initiation Factor eIF4E

“…7,8 Importantly, these elements can be based on sequence features such as the ARE stability element recognized by the HuR (as well as others) protein 9 or structural in nature, as is eIF4E, A Node In An RNA Regulon the 4E-SE. 7 It is important to emphasize that a variety of post-transcriptional processes can be coordinated via recognition of RNAs that contain specific USER codes by proteins that coordinately regulate the expression of this subset of mRNAs. The other critical feature of this model is that gene expression should be combinatorial, i.e., it should be related to the variety of USER codes in the given mRNA.…”

“…For cyclin D1, the region recognized by eIF4E is conserved from humans to chicken. 7 The evolutionary favored length and the complexity of the noncoding regions of mRNA molecules suggest that these evolved to enable the presence of more than one USER code in a given transcript, ergo more regulatory plasticity (i.e., combinatorial). In summary, the USER codes provide a coordinated and combinatorial manner for the cell to regulate expression of genes, and thereby cellular processes.…”

“…7,8,12 As for translational enhancement, eIF4E requires its cap binding activity to promote the export of mRNAs. 7,8 We recently defined a 50 nucleotide structural element in the 3' UTR, we denote the stem loop pair, which is important for the export of at least a subset of eIF4E sensitive mRNAs. 7 This element is referred to as the eIF4E sensitivity element (4E-SE).…”

“…7,8 We recently defined a 50 nucleotide structural element in the 3' UTR, we denote the stem loop pair, which is important for the export of at least a subset of eIF4E sensitive mRNAs. 7 This element is referred to as the eIF4E sensitivity element (4E-SE). 7,8 The 4E-SE acts as a USER code and targets transcripts for eIF4E dependent mRNA export even when fused to lacZ.…”

“…7 This element is referred to as the eIF4E sensitivity element (4E-SE). 7,8 The 4E-SE acts as a USER code and targets transcripts for eIF4E dependent mRNA export even when fused to lacZ. 7,8 As one would predict from different USER codes for translation and export, and the different location of these USER codes in the transcripts, the translation and export activities of eIF4E can be decoupled.…”