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

Abstract

A general increase in protein synthesis and a speci®c increase in the synthesis of growth-promoting proteins are necessary for mitogenesis. Regulation of protein synthesis, as well as preferential translation of some mRNAs coding for growth promoting proteins (e.g. cyclin D1), involves the essential protein synthesis initiation factor eIF-4E. This factor is induced by various oncoproteins, and, when overexpressed, it can transform cultured cells. In this report we explore the roles of eIF-4E in human neoplastic disorders of the colon and in the regulation of general and speci®c protein synthesis. We ®nd that eIF-4E is increased in colon adenomas and carcinomas, and this increase is accompanied in most but not all cases by elevation of cyclin D1 levels. While general protein synthesis is increased by eIF-4E overexpression in cultured cells, only a small proportion of proteins is preferentially upregulated by eIF-4E, as revealed by two-dimensional gel electrophoresis. These results are consistent with the view that eIF-4E plays a role in carcinogenesis by increasing general protein synthesis and by preferentially upregulating a subset of putative growth promoting proteins. Our results, taken together with the recent ®ndings that cmyc transcription is negatively regulated by APC and our earlier data on transcriptional activation of eIF-4E expression by c-Myc suggest that eIF-4E is a downstream target of the APC/b-catenin/Tcf-4 pathway, and is strongly involved in colon tumorigenesis.

Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

“…Where studied, expression of cyclin D1 has been linked to a poor response to therapy and decreased disease-free survival periods (Gansauge et al, 1997;Kornmann et al, 1998;Schuuring et al, 1992). Recent data indicate that eIF4E is increased in colon adenomas and carcinomas, and this increase is accompanied in most but not all cases by elevation in cyclin D1 levels (Rosenwald et al, 1999). These ®ndings support our observation that increased expression of eIF4E does not necessarily upregulate cyclin D1, and also suggest that cyclin D1 mediates some but not all eIF4E e ector pathways leading to tumor formation.…”

eIF4E – from translation to transformation

“…eIF4E is indeed overexpressed in many solid tumors and tumor cell lines. The list includes cancers of the colon, breast, bladder, lung, prostate, gastrointestinal tract, head and neck, Hodgkin's lymphomas and neuroblastomas (Kerekatte et al, 1995;Anthony et al, 1996;De Benedetti and Harris, 1999;Nathan et al, 1999;Rosenwald et al, 1999Rosenwald et al, , 2001Wang et al, 1999Wang et al, , 2001Li et al, 2002a). A role for eIF4E as a prognosis marker has also been suggested in certain cancers (reviewed in Thornton et al, 2003).…”

A cancer gene therapy approach through translational control of a suicide gene

“…4,5 To overcome this problem, the design of an effective cancer gene therapy that permits selective killing of both the primary tumor and distant metastasis must exploit a general characteristic that distinguishes cancer cells from normal cells. Increased expression of the translation initiation factor /proto -oncogene eIF4E has been shown to occur in bladder, 6 breast, 7 cervical, 8 colon, 9 head and neck, 10 and prostate tumors. 11 Therefore, we exploited the ubiquitously increased expression of eIF4E in solid tumors to develop a novel, genetherapy strategy.…”