This study demonstrates that the eukaryotic translation initiation factor eIF4E is a critical node in an RNA regulon that impacts nearly every stage of cell cycle progression. Specifically, eIF4E coordinately promotes the messenger RNA (mRNA) export of several genes involved in the cell cycle. A common feature of these mRNAs is a structurally conserved, ∼50-nucleotide element in the 3′ untranslated region denoted as an eIF4E sensitivity element. This element is sufficient for localization of capped mRNAs to eIF4E nuclear bodies, formation of eIF4E-specific ribonucleoproteins in the nucleus, and eIF4E-dependent mRNA export. The roles of eIF4E in translation and mRNA export are distinct, as they rely on different mRNA elements. Furthermore, eIF4E-dependent mRNA export is independent of ongoing RNA or protein synthesis. Unlike the NXF1-mediated export of bulk mRNAs, eIF4E-dependent mRNA export is CRM1 dependent. Finally, the growth-suppressive promyelocytic leukemia protein (PML) inhibits this RNA regulon. These data provide novel perspectives into the proliferative and oncogenic properties of eIF4E.

The eukaryotic translation initiation factor eIF4E is elevated in 30% of malignancies including M4/M5 subtypes of acute myeloid leukemia (AML). The oncogenic potential of eIF4E arises from its ability to bind the 7-methyl guanosine (m 7 G) cap on mRNAs, thereby selectively enhancing eIF4E-dependent nuclear mRNA export and translation. We tested the clini-

The eukaryotic translation initiation factor eIF4E is deregulated in many human cancers, and its overexpression in cells leads to malignant transformation. Oncogenic properties of eIF4E are directly linked to its ability to bind 7-methyl guanosine of the 5 mRNA. Here, we observe that the antiviral guanosine analogue ribavirin binds to eIF4E with micromolar affinity at the functional site used by 7-methyl guanosine mRNA cap, competes with eIF4E:mRNA binding, and, at low micromolar concentrations, selectively disrupts eIF4E subcellular organization and transport and translation of mRNAs posttranscriptionally regulated by eIF4E, thereby reducing levels of oncogenes such as cyclin D1. Ribavirin potently suppresses eIF4E-mediated oncogenic transformation of murine cells in vitro, of tumor growth of a mouse model of eIF4E-dependent human squamous cell carcinoma in vivo, and of colony formation of eIF4E-dependent acute myelogenous leukemia cells derived from human patients. These findings describe a specific, potent, and unforeseen mechanism of action of ribavirin. Quantum mechanical and NMR structural studies offer directions for the development of derivatives with improved cytostatic and antiviral properties. In all, ribavirin's association with eIF4E may provide a pharmacologic means for the interruption of posttranscriptional networks of oncogenes that maintain and enhance neoplasia and malignancy in human cancer.cancer ͉ drug ͉ virus ͉ oncogenic network W hereas the precise causes of neoplasia and malignancy are known only for a few human cancers, deregulated tumor suppressors and oncogenes that maintain and enhance the malignant phenotype are becoming relatively well described (1, 2). Among these molecules are tumor suppressors like p53, Rb, and APC and oncogenes such as myc, cyclin D1, and eIF4E. Their interactions constitute a network of self-reinforcing feedback loops, whereby inactivation of principal elements can lead to reversal and at times even sustained loss of neoplastic phenotype (3, 4). eIF4E is overexpressed in a wide variety of malignant cell lines and primary human tumors such as carcinomas of the breast (5), colon (6), and head and neck (7), non-Hodgkin's lymphomas (8), and chronic and acute M4͞M5 myelogenous leukemias (9). Consistently, even moderate overexpression of eIF4E in rodent cells leads to deregulated proliferation and malignant transformation (10). eIF4E is essential for growth and survival of eukaryotes by acting at a critical step of cap-dependent translation and recruiting transcripts to the ribosome as a result of a specific interaction with the 5Ј 7-methyl guanosine (m 7 G) mRNA cap (11). It is important to stress that, although the interaction of eIF4E with the 5Ј mRNA cap is required for initiation of translation of cap-dependent mRNAs, up-regulation of eIF4E does not increase translation of all cap-dependent transcripts, but only of a specific subset of eIF4E-sensitive transcripts, as described below.As much as 70% of eIF4E is present in the nuclei of mammalian cells, where it i...