The eukaryotic translation factor eIF4E, a key modulator of cellular growth, is overexpressed in several cancers including some leukemias and breast cancer. eIF4E overexpression in cells leads to promotion of growth and subsequently transformation. Exciting new findings suggest that the oncogenic properties of eIF4E arise not only by promoting growth but also by inhibition of apoptosis. Both its nuclear and cytoplasmic functions contribute to its growth promoting properties. In the cytoplasm, it binds the 7 methyl guanosine (m7G) cap found on the 5' end of all mRNAs thereby allowing translation initiation. Importantly, up to 68% of eIF4E is found in the nucleus, where it promotes mRNA export of a subset of growth promoting transcripts including cyclin D1. This export activity contributes substantially to its transformation activity. We identified a 100 nucleotide element in the non-coding region of target mRNAs which impart sensitivity to eIF4E (allowing preferential export) and refer to this as an eIF4E sensitivity element (4ESE). We postulate that eIF4E's mRNA export function contributes not only to growth but to its survival function. Our preliminary data suggest that mdm2 transcripts, which have putative 4ESEs, are likely regulated by eIF4E at the mRNA export level. This provides at least one mechanism to explain how mRNA export could play a role in survival. Thus, we hypothesize that the survival function of eIF4E in a variety of contexts is due to the repertoire of mRNAs it regulates. Two (2) negative regulators of eIF4E dependent mRNA export and transformation are known from separate studies to be pro-apoptotic: the promyelocytic leukemia protein PML and the proline rich homeodomain PRH /Hex. We postulate their pro-apoptotic activities lie, in part, in their ability to inhibit eIF4E's mRNA export function. We propose three specific aims to investigate these possibilities: 1. Determine whether eIF4E's survival function is mediated, in part, through its ability to promote export of mdm2 mRNA, 2. Establish whether PML and PRH/Hex promote apoptosis through inhibition of eIF4E and 3. Establish the molecular underpinnings of the ability of PML and PRH/Hex to inhibit eIF4E. We believe that elucidation of this regulatory network will yield new insights into eIF4E mediated transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA080728-06A1
Application #
6965063
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
1999-04-01
Project End
2010-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
6
Fiscal Year
2005
Total Cost
$206,550
Indirect Cost
Name
University of Montreal
Department
Type
DUNS #
207622838
City
Montreal
State
PQ
Country
Canada
Zip Code
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:
Borden, Katherine L B (2016) The eukaryotic translation initiation factor eIF4E wears a ""cap"" for many occasions. Translation (Austin) 4:e1220899
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
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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