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A central issue in the study of neoplastic transformation is to understand how proto-oncogene products deregulate normal processes of cell growth and differentiation: an intrinsic aspect of this is to probe the sequence of events leading to altered expression of proto-oncogenes. In the past few years, studies aimed at understanding the regulation and function of protein synthesis initiation factors, eIF4E initially, 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 cancer cells can be strongly inhibited by antisense-RNA against eIF4E, or overexpression of the inhibitory proteins: 4E-BPs. Furthermore, eIF4E is elevated in carcinomas of the breast, head and neck (HNSCC) and prostate, but not in typical benign lesions. This is a strong indication that elevated eIF4E expression may mark a critical transition in cancer progression. Establishing a greater protein synthesis output may be a necessary step for cancer cells in order to sustain their rapid proliferation. However, analysis of cells transformed by eIF4E revealed that the synthesis of only a few proteins was greatly enhanced, while synthesis of most was minimally increased. One possible explanation is that eIF4E causes 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 several important products that are specifically upregulated in eIF4E-overexpressing cells. These include: c-Myc, cyclin DI and ODC, which control cycle progression and tumorigenesis; basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF), which are powerful promoters of cell growth and angiogenesis. A deeper understanding of the mRNAs that are strongly dependent on excess eIF4E/F for efficient translation will eventually result in fuller understanding of the fundamental role of translational control in different pathophysiological conditions, including malignancy.

Original publication

DOI

10.1016/s1357-2725(98)00132-0

Type

Journal article

Journal

Int J Biochem Cell Biol

Publication Date

01/1999

Volume

31

Pages

59 - 72

Keywords

Animals, Apoptosis, Breast Neoplasms, Carcinoma, Cell Division, Cyclin D1, Disease Progression, Endothelial Growth Factors, Eukaryotic Initiation Factor-4E, Fibroblast Growth Factor 2, Gene Expression Regulation, Neoplastic, Genes, myc, Head and Neck Neoplasms, Humans, Lymphokines, Metalloendopeptidases, Neoplasm Proteins, Neoplasms, Peptide Initiation Factors, RNA, Messenger, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors