Control of Protein Synthesis in Malignant Transformation - the Role of eIF4E and the eIF4E Binding Proteins in the Regulation of Apoptosis

Michael J. Clemens; Androulla Elia; Constantina Constantinou

Abstract

Tumour cells are frequently characterized by over-expression of the polypeptide chain initiation factor eIF4E and current evidence supports the view that this factor contributes to malignant transformation. The availability of eIF4E for protein synthesis is regulated by the 4E binding proteins. The ability of these proteins to bind eIF4E is inhibited by multi-site phosphorylation, catalysed by the mammalian target of rapamycin (mTOR) and other protein kinases. This phosphorylation is stimulated by growth factors and nutrients whereas dephosphorylation is activated by a variety of cellular stresses. Over-expression of eIF4E promotes resistance to apoptosis, most likely as a result of enhanced synthesis of growth-promoting and anti-apoptotic proteins. Conversely, increased levels of the 4E binding proteins can promote apoptosis and suppress tumourigenicity. Consistent with this, the mTOR inhibitor rapamycin can enhance cell death, especially in cells in which signal transduction pathways that activate mTOR are hyperactive, and analogues of rapamycin are now in clinical use against a number of human cancers. Recent evidence suggests that phosphorylation may also reduce the stability of the 4E binding proteins, as a consequence of increased susceptibility to ubiquitination and subsequent degradation. Such accelerated degradation would result in greater availability of eIF4E for translation and the inhibition of apoptosis.

Keywords: Cancer, mTOR, oncogene, protein phosphorylation, therapy, translational control