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.
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.
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