An important issue in the study of neoplastic transformation is understanding how proto-oncogene products deregulate normal processes of growth and differentiation. During the past few years, studies aimed at understanding the regulation and functions of the protein synthesis initiation factor eIF-4E culminated in the unexpected finding that a moderate overexpression of this factor results in dramatic phenotypic changes, including rapid proliferation and malignant transformation. Conversely, the tumorigenic properties of model cells transformed with ras were strongly inhibited by antisense-RNA against eIF-4E. Furthermore, we recently found that eIF-4E was elevated 3 to 30-fold in breast carcinomas, but not in benign adenomas, indicating that an elevated eIF-4E expression may mark a critical transition in the genesis of breast cancer. Establishing greater protein synthesis outputs may be a necessary development which cancer cells must accomplish in order to sustain their rapid proliferation. eIF-4E may cause these effects by specifically increasing the translational efficiency of several oncogene transcripts, leading to overexpression of their products. The feasibility of this hypothesis was confirmed experimentally with the identification of two important products which are upregulated in eIF-4E-overexpressing cells: c-Myc, which controls cell cycle progression and tumorigenesis, and basic fibroblast growth factor (FGF-2), a powerful promoter of cell growth and angiogenesis. They now propose to analyze breast biopsies containing cells at different stages of dysplasia and neoplasia to determine the expression of eIF-4E. This will help to determine the stage at which eIF-4E becomes elevated, and to establish the feasibility of using eIF-4E as a marker for early cancer detection. They will also generate and study breast cell lines to establish how eIF-4E affects their tumorigenic and metastatic properties. This will be accomplished primarily with the use of expression vectors and antisense RNA technology, to either elevate or reduce the level of eIF-4E. For this work they will use an episomal expression vector that they developed to give strong and inducible expression in transfected human cells. They will also measure the expression of FGF-2, which is strongly dependent on eIF-4E, as a reporter for eIF-4E activity.
| De Benedetti, Arrigo (2012) The Tousled-Like Kinases as Guardians of Genome Integrity. ISRN Mol Biol 2012:627596 |
