. The eukaryotic translation initiation factor eIF4E, a key modulator of cellular growth, is elevated in several cancers including some leukemias and breast cancer. eIF4E overexpression in cells promotes proliferation and subsequently transformation. eIF4E is a network node in a RNA regulon promoting proliferation and survival by the coordinated upregulation of the expression of genes involved in these pathways. eIF4E functions in both the nucleus and cytoplasm. In the cytoplasm, it binds the 7 methyl guanosine (m7G) cap found on the 5'end of 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 cyclins D1, A2, B1, mdm2, c-myc etc. This mRNA export activity contributes substantially to its transformation activity. We identified a 50 nucleotide element in the untranslated region of target mRNAs which impart sensitivity to eIF4E (allowing preferential export) and refer to this as an eIF4E sensitivity element (4E- SE). Thus, eIF4E can coordinately upregulate expression of genes which contain the 4E-SE. eIF4E is dysregulated at (least) three levels in a subset of leukemias: eIF4E is highly elevated, its subcellular distribution is altered where it accumulates in the nucleus and regulation of its activity by binding partners is altered. Here, we will examine the molecular basis for this dysregulation. Further we will determine the effects of this dysregulation on eIF4E function. We identified a novel means to elevate eIF4E levels, through increased eIF4E mRNA stability via interactions with the mRNA stability factor HuR. Like eIF4E, HuR is a potent proto-oncogene. Next, we will examine the means the cell uses to regulate localization and thus function of eIF4E and whether this is dysregulated in these cancers. Finally, we will examine the impact of a novel nuclear partner of eIF4E on its activities. We propose three specific aims to investigate these possibilities: 1. Establish whether HuR modulates eIF4E's activity 2. Establish whether the eIF4E transporter protein, 4E-T, modulates eIF4E function as well as its localization and 3. Examine novel modes of control of nuclear eIF4E by the eIF4E binding protein BP1. We believe that elucidation of this regulatory network will yield new insights into eIF4E mediated transformation. Further, these findings could provide novel therapeutic strategies for cancers characterized by dysregulated eIF4E.

Public Health Relevance

. The eukaryotic translation initiation factor eIF4E is dysregulated in many human cancers including cancers of the breast, head &neck, colon, prostate and blood. Our project is designed to understand the mechanisms and therapeutic implications of this dysregulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA098571-10
Application #
8465821
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Strasburger, Jennifer
Project Start
2002-12-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$202,079
Indirect Cost
$14,970
Name
University of Montreal
Department
Type
DUNS #
207622838
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 3-J7
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
Delaleau, Mildred; Borden, Katherine L B (2015) Multiple Export Mechanisms for mRNAs. Cells 4:452-73
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
Borden, Katherine L B (2014) When will resistance be futile? Cancer Res 74:7175-80
Zahreddine, Hiba Ahmad; Culjkovic-Kraljacic, Biljana; Assouline, Sarit et al. (2014) The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature 511:90-3
Volpon, Laurent; Osborne, Michael J; Zahreddine, Hiba et al. (2013) Conformational changes induced in the eukaryotic translation initiation factor eIF4E by a clinically relevant inhibitor, ribavirin triphosphate. Biochem Biophys Res Commun 434:614-9
Romeo, Y; Moreau, J; Zindy, P-J et al. (2013) RSK regulates activated BRAF signalling to mTORC1 and promotes melanoma growth. Oncogene 32:2917-26
Culjkovic-Kraljacic, Biljana; Borden, Katherine L B (2013) Aiding and abetting cancer: mRNA export and the nuclear pore. Trends Cell Biol 23:328-35
Hariri, F; Arguello, M; Volpon, L et al. (2013) The eukaryotic translation initiation factor eIF4E is a direct transcriptional target of NF-κB and is aberrantly regulated in acute myeloid leukemia. Leukemia 27:2047-55

Showing the most recent 10 out of 17 publications