Translational regulation of vascular permeability factor by eukaryotic initiation factor 4E: Implications for tumor angiogenesis

Abstract

Studies aimed at elucidating the function of the protein synthesis factor eukaryotic initiation factor 4E (eIF-4E) have demonstrated that overexpression of this protein results in marked cell phenotypic and proliferative changes, including neoplastic transformation of cells. These data suggest that eIF-4E may somehow participate in the development and progression of tumors in vivo. In order to determine how eIF-4E exerts its transforming effects, we examined vascular permeability factor (VPF) levels in cells transfected with an eIF-4E vector. Cells overexpressing eIF-4E showed an increase in intracellular, and an average 130-fold increase in secreted VPF protein levels (CHO 0.13 ± 0.12 ng/ml; CHO-4E 20.5 ± 12.5 ng/ml) over control cells. HUVEC growth induction revealed these VPF levels to be biologically active. Northern analysis revealed no difference in VPF transcript between the 2 cell lines. Polysome analysis showed that the VPF message in eIF-4E-transfected cells was associated with the heavy polysomal regions, whereas the VPF message was associated with light polysomes in control cells. These data strongly suggest that enhanced VPF expression is achieved through translational regulation rather than transcriptional regulation in cells overexpressing eIF-4E. This indicates that eIF-4E-induced VPF expression may be an important factor in some forms of tumor angiogenesis and development.