Overview
Translational control: the cancer connection

https://doi.org/10.1016/S1357-2725(98)00127-7Get rights and content

Abstract

There is now a growing body of evidence which suggests links between the regulation of protein synthesis and the disruption of cell behaviour that typifies cancer. This directed issue of the International Journal of Biochemistry and Cell Biology presents several review articles of relevance to this field. The topics covered include the significance of the regulation and overexpression of polypeptide chain initiation factors for cell transformation and malignancy, the role of mRNA structure in the control of synthesis of key growth regulatory proteins, the actions of the eIF2 alpha-specific protein kinase PKR in the control of cell growth and apoptosis, and the involvement of the elongation factor eEF1 in oncogenesis. The purpose of this article is to give an overview of the field and to indicate where we may expect developments to occur in the next few years.

Section snippets

The protein synthesis pathway in eukaryotes

For detailed coverage of the events involved in mRNA translation the reader is referred to recent comprehensive reviews2, 9. Here we provide a brief overview only.

In order for translation to take place three components, viz. the ribosome, the mRNA template and aminoacylated tRNAs, have to be brought together in the correct configuration. This is achieved by means of the involvement of a large number of proteins which bind one or more of these components. In the initiation phase of protein

Growth-related regulation of translation

The pathway by which polypeptide chains are assembled is subject to regulation at several key steps. Events required for the initiation of protein synthesis are generally regarded as the rate-limiting steps, with particular attention being paid to the role of phosphorylation of the smallest (α) subunit of eIF2[12], the control of the activity of the guanine nucleotide exchange factor eIF2B[11], and the availability or activity of the cap-binding factor eIF4E13, 14. It is likely, however, that

Translation factors as proto-oncogenes

In view of the fact that translation factors are closely regulated by conditions that affect cell growth, it is not surprising that, experimentally, aberrant expression of some of these factors has been shown to induce malignant transformation of cells. Overexpression of eIF4E[25]or eIF4G[26]has been shown to result in transformation of NIH-3T3 cells (although in the latter case the cells were selected initially for their ability to grow in soft agar rather than for eIF4G expression per se so

Translation factor levels are elevated in many tumours

The demonstration that eIF4E overexpression leads to transformation of cells in culture gave rise to various additional questions, for example: Are levels of eIF4E (and of other translation factors) actually elevated in human tumours? What are the underlying mechanisms? Is the rise in eIF4E levels/activity a cause or a consequence of malignant transformation? How does elevation of eIF4E levels confer the transformed phenotype? Although not all of these question can be answered completely yet, a

Mechanisms of translational regulation of specific mRNAs whose products are important for cell growth

As pointed out in the preceding section, there is now overwhelming evidence that (constitutive) activation of the cap-dependent mRNA unwinding machinery is a crucial step in transformation of cells, most likely due to translational activation of the otherwise poorly translated mRNAs of growth-promoting genes. However, apart from unwinding of secondary structure, there are also other mechanisms operating to activate selectively the translation of `weak' mRNAs. A comprehensive compilation of

Growth factors and components of signal transduction pathways

Expression of the genes of many growth factors and cytokines has been shown to be translationally regulated (reviewed in[80]in this issue). A well-studied example is fibroblast growth factor-2 (FGF-2) whose translation can be initiated both at the `normal' AUG codon or at several upstream CUG codons of the mRNA[121]. Recently it was shown that this mechanism is mediated by an internal ribosome entry site[122]. The four resulting forms of the FGF-2 protein differ in their subcellular localisation

Future directions

In this overview article we have highlighted those areas of research into the mechanisms and regulation of translation that are most relevant to the cancer problem, and we have indicated where these topics are covered in greater depth in the accompanying reviews in this issue. It seems likely that this field is still in its relative infancy and that many more aspects of the regulation of gene expression at the level of protein synthesis will be found to be relevant to experimental or clinical

Acknowledgements

We are grateful to Dr. S. Morley and Dr. V.M. Pain (University of Sussex) for permission to modify figures that have appeared elsewhere in articles written by these authors. Research in our laboratories is supported by The Wellcome Trust, The Leukaemia Research Fund, The Cancer Prevention Research Trust and Glaxo-Wellcome.

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