Stability of Eukaryotic Translation Initiation Factor 4E mRNA Is Regulated by HuR, and This Activity Is Dysregulated in Cancer

Abstract

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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We are grateful to Serafin Piñol-Roma (anti-hnRNP A1 [4B10] and anti-hnRNP C1/C2 [4F4] antibodies), Jack Keene (3A2 anti-HuR antibody and pcDNA/HuR construct), and Gary Brewer (pcDNA/AUF1 constructs). We thank Christian Charbonneau for help with microscopy, Matthew Friedersdorf for help with the COVELs algorithm, and Jack D. Keene for helpful discussions.

This work is supported by funding from NIH (RO1 R56 98571) to K.L.B.B. She holds a Canada Research Chair in Molecular Biology of the Cell Nucleus. I.T. is a Special Fellow of the Leukemia and Lymphoma Society of the United States. T.H. is supported by grants from the Canadian Institute for Health Research (CIHR) and from the National Cancer Institute of Canada. She holds a Canada Research Chair in Cell Differentiation and the Genetics of Acute Leukemias. M.T. is supported by a studentship award from the Fonds de Recherche en Santé du Québec and the CIHR.