Rates of eukaryotic protein synthesis and proliferation are dependent upon the availability of eIF4F, the cap-binding translation initiation complex that guides the ribosome onto the mRNA. One possible rate-limiting factor in eIF4F complex formation is the availability of eIF4E, which interacts specifically with the mRNA cap structure. As such, it has a potential role in the selective translation of growth-related mRNAs, with overexpression of eIF4E resulting in aberrant cell growth and transformation. A number of studies suggest that eIF4E may play a role in cellular differentiation as well as proliferation. We have previously reported that post-transcriptional regulation is involved in the induction of keratins in epithelial lung tumor cell lines exposed to the differentiation-modulating agent, bromo-deoxyuridine (BrdU). Here, we demonstrate that these BrdU-treated lung cells express elevated levels of eIF4E protein and enhanced phosphorylation of eIF4E. Overexpression of eIF4E by cDNA transfection in the poorly differentiated, keratin-negative human lung cell line, DLKP, was found to promote a flattened, more epithelial appearance to these cells, coupled with the induction of simple keratins (keratins 8 and 18). In contrast, levels of eIF4E expression were found to decrease during BrdU-induced differentiation of the leukemic cell line, HL-60, suggesting that there are cell-type differences in the response to BrdU and in the requirement for eIF4E during differentiation.