Eukaryotic translation
initiation factor 4E (
eIF4E) is encoded by a potent oncogene which is highly elevated in many human
cancers. Few studies have investigated how the level, and thus activity, of
eIF4E is regulated in healthy (noncancerous) cells and how they become elevated in malignant cells. Here, our studies reveal a novel mechanism by which
eIF4E levels are regulated at the level of mRNA stability. Two factors known to modulate transcript stability, HuR and the p42
isoform of AUF1, compete for binding to the
3' untranslated regions (
3'UTRs) of
eIF4E mRNAs. We identified a distinct AU-rich element in the
3'UTR of
eIF4E which is responsible for HuR-mediated binding and stabilization. Our studies show that HuR is upregulated in malignant
cancer specimens characterized by high
eIF4E levels and that its depletion leads to reduction in
eIF4E levels. Further, HuR and
eIF4E regulate a common set of transcripts involved in cellular proliferation (
cyclin D1 and c-myc) and neoangiogenesis (
vascular endothelial growth factor), which suggests a functional connection between HuR and
eIF4E in the regulation of these important processes. In summary, we present a novel model for the regulation of
eIF4E expression and show that this model is relevant to elevation of
eIF4E levels in malignant cells.