. 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.
. 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.
|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|
|Culjkovic-Kraljacic, Biljana; Borden, Katherine L B (2013) Aiding and abetting cancer: mRNA export and the nuclear pore. Trends Cell Biol 23:328-35|
|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|
|Borden, Katherine L B; Culjkovic-Kraljacic, Biljana (2010) Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond? Leuk Lymphoma 51:1805-15|
|Borden, Katherine L B (2008) Pondering the puzzle of PML (promyelocytic leukemia) nuclear bodies: can we fit the pieces together using an RNA regulon? Biochim Biophys Acta 1783:2145-54|
|Tan, Keith; Culjkovic, Biljana; Amri, Abdellatif et al. (2008) Ribavirin targets eIF4E dependent Akt survival signaling. Biochem Biophys Res Commun 375:341-5|
|Culjkovic, Biljana; Topisirovic, Ivan; Skrabanek, Lucy et al. (2006) eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 175:415-26|
|Topisirovic, Ivan; Kentsis, Alex; Perez, Jacqueline M et al. (2005) Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels. Mol Cell Biol 25:1100-12|
|Kentsis, Alex; Topisirovic, Ivan; Culjkovic, Biljana et al. (2004) Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci U S A 101:18105-10|