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Molecular and Cellular Biology, March 2009, p. 1152-1162, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01532-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Ivan Topisirovic,1,2,# Nadeem Siddiqui,1,2,# Slobodanka Orolicki,1,2 Lucy A. Skrabanek,5,6 Mathieu Tremblay,1,3 Trang Hoang,1,3,4 and Katherine L. B. Borden1,2*

Institute for Research in Immunology and Cancer,1 Department of Pathology and Cell Biology,2 Molecular Biology Program,3 Departments of Pharmacology and Biochemistry, Université de Montréal, Montréal, Québec H3T 1J4, Canada,4 Department of Physiology and Biophysics,5 HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College, Cornell University, New York, New York 100216

Received 1 October 2008/ Returned for modification 17 November 2008/ Accepted 17 December 2008

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.

* Corresponding author. Mailing address: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada. Phone: (514) 343-6291. Fax: (514) 343-5839. E-mail: katherine.borden{at}umontreal.ca

{triangledown} Published ahead of print on 29 December 2008.

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

# These two authors contributed equally to this work.

Molecular and Cellular Biology, March 2009, p. 1152-1162, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01532-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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