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eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3'UTR

¹ Institute for Research in Immunology and Cancer, University of Montreal, Quebec, H3T 1J4 Canada
² Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029
³ Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY 10021

Correspondence to Katherine L.B. Borden: Katherine.Borden{at}umontreal.ca

The eukaryotic translation initiation factor eIF4E is a critical modulator of cellular growth with functions in the nucleus and cytoplasm. In the cytoplasm, recognition of the 5' m⁷G cap moiety on all mRNAs is sufficient for their functional interaction with eIF4E. In contrast, we have shown that in the nucleus eIF4E associates and promotes the nuclear export of cyclin D1, but not GAPDH or actin mRNAs. We determined that the basis of this discriminatory interaction is an 100-nt sequence in the 3' untranslated region (UTR) of cyclin D1 mRNA, we refer to as an eIF4E sensitivity element (4E-SE). We found that cyclin D1 mRNA is enriched at eIF4E nuclear bodies, suggesting these are functional sites for organization of specific ribonucleoproteins. The 4E-SE is required for eIF4E to efficiently transform cells, thereby linking recognition of this element to eIF4E mediated oncogenic transformation. Our studies demonstrate previously uncharacterized fundamental differences in eIF4E-mRNA recognition between the nuclear and cytoplasmic compartments and further a novel level of regulation of cellular proliferation.

Abbreviations used in this paper: CBC, cap-binding complex; ODC, ornithine decarboxylase; SNAAP, specific nucleic acids associated with protein; UTR, untranslated region.

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