Regulation of protein synthesis and the role of eIF3 in cancer

John W.B Hershey

doi:10.1590/s0100-879x2010007500098

Abstract

Maintenance of cell homeostasis and regulation of cell proliferation depend importantly on regulating the process of protein synthesis. Many disease states arise when disregulation of protein synthesis occurs. This review focuses on mechanisms of translational control and how disregulation results in cell malignancy. Most translational controls occur during the initiation phase of protein synthesis, with the initiation factors being the major target of regulation through their phosphorylation. In particular, the recruitment of mRNAs through the m⁷G-cap structure and the binding of the initiator methionyl-tRNA(i) are frequent targets. However, translation, especially of specific mRNAs, may also be regulated by sequestration into processing bodies or stress granules, by trans-acting proteins or by microRNAs. When the process of protein synthesis is hyper-activated, weak mRNAs are translated relatively more efficiently, leading to an imbalance of cellular proteins that promotes cell proliferation and malignant transformation. This occurs, for example, when the cap-binding protein, eIF4E, is overexpressed, or when the methionyl-tRNA(i)-binding factor, eIF2, is too active. In addition, enhanced activity of eIF3 contributes to oncogenesis. The importance of the translation initiation factors as regulators of protein synthesis and cell proliferation makes them potential therapeutic targets for the treatment of cancer.

Highlights

Protein synthesis is an important step in gene expression, as it plays a pivotal role in establishing cellular protein levels and in defining the differentiated characteristics of cells
EIF3e binds to P56, an interferon-induced protein that inhibits protein synthesis [46]. eIF3g binds to PAIP, a polyA binding protein (PABP)-binding protein that stimulates initiation [47]; in addition, plant eIF3g binds to TAV, required for shunting of the 40S initiation complex during scanning/reinitiation [48]. eIF3f binds to Atrogina/MAFbx, a ubiquitin E3 ligase that degrades the subunit during muscle atrophy [49]
The results indicate that elevated levels of eIF3h are required to maintain the cancerous state of these prostate-derived cells

Summary

Introduction

Protein synthesis is an important step in gene expression, as it plays a pivotal role in establishing cellular protein levels and in defining the differentiated characteristics of cells. Protein synthesis is closely integrated with other metabolic pathways, influencing transcription, protein turnover, early development and neurological function, inter alia It employs a massive apparatus and is a major consumer of energy. In order to maintain cell homeostasis, it is essential to regulate the overall rate of protein synthesis, with special attention to the need for new proteins and to the availability of amino acids and energy Such regulation, called translational control, is the topic of this review. Some well-documented cases include mutations in or around initiation codons that directly contribute to human disease [1] In such cases, the overall process of protein synthesis is normal, with only the mutated gene product being affected. A major challenge in studies of protein synthesis is to understand the process of protein synthesis in sufficient detail and precision in order to be able to detect the subtle changes that are responsible for certain disease states

In addition to being caused by a defect in the apparatus

How to measure translational control

Brief review of the pathway and mechanism of initiation

Regulation of general protein synthesis by phosphorylation

Other mechanisms involving protein synthesis and cancer