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

Oncogene volume 18, pages 2507–2517 (1999)Cite this article

Abstract

A general increase in protein synthesis and a specific 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 specific protein synthesis. We find 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 up-regulated 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 findings that c-myc 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/β-catenin/Tcf-4 pathway, and is strongly involved in colon tumorigenesis.

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Acknowledgements

This work was supported in part by Johnson & Johnson grant to IBR, UMMC Pathology Department Teaching Grant to JP and IBR, and NIH grant DK 16272 to J-J C. We thank Dr Kenneth L Rock (Department of Pathology, University of Massachusetts Medical Center) for his support and advice during this work. We express our gratitude to Dr Nahum Sonenberg and Dr Anne-Claude Gingras (McGill University, Montreal) for providing anti eIF-4E polyclonal antibodies. We are grateful to Dr German Pihan and Jane Wallace (Pathology Department, University of Massachusetts Medical Center) for their help in processing of frozen tissues into protein lysates and Karen Graham and Kristine Israelian (same department) for their assistance in performing immunohistochemical analysis. We also thank Maryam Rafie-Kolpin (Harvard-MIT Division of Health Sciences and Technology) and Robin Ganesan (University of Massachusetts, Department of Molecular Genetics and Microbiology) for their help in scanning and densitometric evaluation of 2D gels and Western blots. We wish to thank Dr James Michaelson (MGH Cancer Center, Harvard Medical School), Dr Roger Kaspar (Brigham Young University, Provo) and Dr Michael Hatzler (Department of Pathology, University of Massachusetts Medical Center) for critically reading this manuscript.

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  1. Igor B Rosenwald: Address after July 1 1999: Beth Israel-Deaconess Medical Center, Harvard Medical School, Clinical Pathology Division of Hematopathology, YA-309, 330 Brookline Ave., Boston MA 02215, USA

Authors and Affiliations

  1. Department of Pathology, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, 01655, Massachusetts, USA

    Igor B Rosenwald, Songtao Wang, Lou Savas & James Pullman

  2. Division of Health Sciences and Technology, Harvard University-Massachusetts Institute of Technology, Room E25-545, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Igor B Rosenwald, Jane-Jane Chen & Irving M London

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Rosenwald, I., Chen, JJ., Wang, S. et al. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 18, 2507–2517 (1999). https://doi.org/10.1038/sj.onc.1202563

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