The eukaryotic translation initiation factor eIF4E is an oncogene which drives the expression of proteins involved in proliferation and survival. Specifically, eIF4E drives expression at the levels of translation and nuclear export of specific transcripts encoding growth-promoting proteins. This activity requires an interaction with the m7G cap on the 5' end of mRNAs. During the past 15 years of this grant, we demonstrated that the mRNA export function of eIF4E contributes to its oncogenic potential. These studies led to the identification of a cap competitor, ribavirin, which suppresses eIF4E activity in the laborator and in two clinical trials in poor prognosis M4/M5 AML patients. Clinically, eIF4E targeting corresponded to responses including remissions. Given its clear relevance, we initiated studies to dissect the molecular underpinnings of eIF4E mediated RNA export. Using a proteomics approach to identify export relevant co-factors, we identified the enzyme RNMT. This enzyme plays a critical step in the production of the m7G cap, by methylating the 5' guanosine. m7G capping is an important step in mRNA maturation and is required for nearly all aspects of mRNA metabolism including mRNA export, translation and stability. The m7G cap is required for eIF4E to bind its target RNAs. Given this, we postulated that eIF4E modified capping of its own target mRNAs. We show here that this is indeed the case. In the 40 years since eIF4E was first identified, no such activity has ever been reported. Our initial findings that eIF4E physically associates with RNMT in the nucleus and directly binds RNMT in vitro, support the notion that eIF4E directly modulates RNMT activity and thus, potentially cellular cap production. In addition, our preliminary data indicate that eIF4E can drive the mRNA export of RNMT transcripts suggesting that it modulates RNMT activity both through direct interactions and at the level of RNMT expression. Here, we will examine the biochemical and cellular underpinnings of these process and characterize the relevant regulatory mechanisms keeping this eIF4E activity in check. We postulate that elucidating the molecular underpinnings and regulation of this process will provide novel insights into the underlying basis of eIF4E mediated oncogenic transformation.

Public Health Relevance

eIF4E is elevated in an estimated 30% of cancers including acute myeloid leukemias (AML) of the M4 and M5 subtype. Studies of eIF4E elevation in cell culture and animal models demonstrate that it is a potent oncogene. Targeting of eIF4E led to remissions in some AML patients thus understanding its molecular activities is important.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080728-18
Application #
9437710
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Strasburger, Jennifer
Project Start
1999-04-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Montreal
Department
Type
DUNS #
207622838
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 3J7
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

Showing the most recent 10 out of 50 publications