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.
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