The eukaryotic initiation factor eIF4E is a key regulator of cellular growth elF4E is overexpressed in several cancers. Its overexpression results in oncogenic transformation of a variety of cell lines. This protein functions in the rate limiting step of translation initiation where it binds the 7 methyl guanosine cap moiety (m7G cap) found on all mRNAs thereby allowing the given mRNA to be translated. The effects of eIF4E on translation are not uniform, where eIF4E overexpression upregulates translation of specific transcripts more so than others. Transcripts with complex untranslated regions (UTRs) in particular are more sensitive to eIF4E levels. In general housekeeping genes do not have complex UTRs, however, several growth control proteins, such as the cyclins, do. Traditionally, elF4E transforms cells by inappropriate translation of transcripts that promote growth. However, exciting new findings indicate that a substantial fraction (up to 68%) of eIF4E forms nuclear bodies and that this fraction promotes the transport of specific transcripts, such as cyclin D1, from the nucleus to the cytoplasm without affecting transport of housekeeping genes such as GAPDH and actin. Again, the specificity appears to be mediated by the UTR structure. Our studies indicate that mutations, which disrupt the ability of eIF4E to act in translation do not disrupt its ability to transform cells. These findings represent a major paradigm shift in that eIF4E can transform cells independently of its translation functions. We hypothesize that eIF4E promotes transformation at least in part through its ability to promote the transport of growth specific mRNAs, eIF4E nuclear bodies co-localize with those containing the promyelocytic leukemia protein PML. PML is a potent negative regulator of the transport and transformation activity of eIF4E. The RING domain of PML binds directly to eIF4E, alters its conformation, reduces m7G cap mRNA affinity and suppresses transport and transformation. In addition, the myeloid specific proline rich homeodomain protein PRH, which functions in hematopoiesis binds directly to eIF4E, reduces its affinity for the m7G cap and decreases cyclin D1 mRNA transport. PRH uses a conserved eIF4E, binding site to directly bind eIF4E. Data base analysis indicates that about 200 homeodomain proteins have this site. Thus, we hypothesize that eIF4E, through interactions with these proteins plays a key rote in differentiation. We propose to 1. Determine the role of nuclear functions of eIF4E in terms of its transformation potential, 2. Determine whether eIF4E plays a role in hematopoiesis through its interactions with PRH and 3. Determine whether other homeodomains modulate eIF4E function. We believe that elucidation of the regulatory network in which elF4E functions will yield broad insights into normal growth control and differentiation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Perry, Mary Ellen
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University of Montreal
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H3 3-J7
Osborne, Michael J; Coutinho de Oliveira, Luciana; Volpon, Laurent et al. (2018) Overcoming Drug Resistance through the Development of Selective Inhibitors of UDP-Glucuronosyltransferase Enzymes. J Mol Biol :
Osborne, Michael J; Coutinho de Oliveira, Luciana; Volpon, Laurent et al. (2018) Backbone assignment of the apo-form of the human C-terminal domain of UDP-glucuronosyltransferase 1A (UGT1A). Biomol NMR Assign :
Volpon, Laurent; Culjkovic-Kraljacic, Biljana; Sohn, Hye Seon et al. (2017) A biochemical framework for eIF4E-dependent mRNA export and nuclear recycling of the export machinery. RNA 23:927-937
Zahreddine, Hiba Ahmad; Culjkovic-Kraljacic, Biljana; Emond, Audrey et al. (2017) The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity. Elife 6:
Culjkovic-Kraljacic, Biljana; Fernando, Tharu M; Marullo, Rossella et al. (2016) Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. Blood 127:858-68
Volpon, Laurent; Culjkovic-Kraljacic, Biljana; Osborne, Michael J et al. (2016) Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E. Proc Natl Acad Sci U S A 113:5263-8
Borden, Katherine L B (2016) The eukaryotic translation initiation factor eIF4E wears a ""cap"" for many occasions. Translation (Austin) 4:e1220899
Zahreddine, Hiba Ahmad; Borden, Katherine L B (2015) Molecular Pathways: GLI1-Induced Drug Glucuronidation in Resistant Cancer Cells. Clin Cancer Res 21:2207-10
Osborne, Michael J; Borden, Katherine L B (2015) The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled. Immunol Rev 263:210-23
Delaleau, Mildred; Borden, Katherine L B (2015) Multiple Export Mechanisms for mRNAs. Cells 4:452-73

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