ABSTRACT
The
eukaryotic translation initiation factor 4E (eIF4E) acts as both a key
translation factor and as a promoter of nucleocytoplasmic transport of
specific transcripts. Traditionally, its transformation capacity in
vivo is attributed to its role in translation initiation in the
cytoplasm. Here, we demonstrate that elevated eIF4E impedes
granulocytic and monocytic differentiation. Our subsequent mutagenesis
studies indicate that this block is a result of dysregulated
eIF4E-dependent mRNA transport. These studies indicate that the RNA
transport function of eIF4E could contribute to leukemogenesis. We
extended our studies to provide the first evidence that the nuclear
transport function of eIF4E contributes to human malignancy,
specifically in a subset of acute and chronic myelogenous leukemia
patients. We observe an increase in eIF4E-dependent cyclin D1 mRNA
transport and a concomitant increase in cyclin D1 protein levels. The
aberrant nuclear function of eIF4E is due to abnormally large eIF4E
bodies and the loss of regulation by the proline-rich homeodomain PRH.
We developed a novel tool to modulate this transport activity. The
introduction of IκB, the repressor of NF-κB, leads to
suppression of eIF4E, elevation of PRH, reorganization of eIF4E nuclear
bodies, and subsequent downregulation of eIF4E-dependent mRNA
transport. Thus, our findings indicate that this nuclear function of
eIF4E can contribute to leukemogenesis by promoting growth and by
impeding
differentiation.