Targets and mechanisms for the regulation of translation in malignant transformation.

There is increasing evidence that deregulation of gene expression at the level of mRNA translation can contribute to cell transformation and the malignant phenotype. Two steps in the pathway of polypeptide chain initiation, viz. the assembly of the 43S initiation complex catalysed by polypeptide chain initiation factor eIF2 and the binding of eIF4E to eIF4G during the recruitment of mRNA to the ribosome, have been shown to be likely targets for changes associated with tumorigenesis. The activity of eIF2 is controlled by changes in phosphorylation of the alpha subunit of this factor. The availability of eIF4E for binding to eIF4G is regulated by the phosphorylation of a small family of eIF4E-binding proteins (the 4E-BPs). The activities of the protein kinases and/or phosphatases responsible for the (de)phosphorylation of these substrates may in turn be controlled by cellular and viral oncogenes and tumour-suppressor genes. This review will describe recent aspects of the mechanisms involved, with particular emphasis on the regulation of the eIF2 alpha kinase PKR and the control of 4E-BP phosphorylation by viral gene products, growth-inhibitory cytokines and the tumour-suppressor protein p53.