Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis

A general increase in protein synthesis and a specific increase in the synt hesis of growth-promoting proteins are necessary for mitogenesis, Regulatio n of protein synthesis, as well as preferential translation of some mRNAs c oding for growth promoting proteins (e.g. cyclin D1), involves the essentia l protein synthesis initiation factor eIF-4E. This factor is induced by var ious oncoproteins, and, when overexpressed, it can transform cultured cells . In this report we explore the roles of eIF-4E in human neoplastic disorde rs of the colon and in the regulation of general and specific protein synth esis, We find that eIF-4E is increased in colon adenomas and carcinomas, an d this increase is accompanied in most but not all cases by elevation of cy clin D1 levels. While general protein synthesis is increased by eIF-4E over expression in cultured cells, only a small proportion of proteins is prefer entially upregulated by eIF-4E, as revealed by two-dimensional gel electrop horesis. These results are consistent with the view that eIF-4E plays a rol e in carcinogenesis by increasing general protein synthesis and by preferen tially upregulating a subset of putative growth promoting proteins. Our res ults, taken together with the recent findings that c-myc transcription is n egatively regulated by APC and our earlier data on transcriptional activati on of eIF-4E expression by c-Myc suggest that eIF-4E is a downstream target of the APC/beta-catenin/Tcf-4 pathway, and is strongly involved in colon t umorigenesis.