Translation initiation and its deregulation during tumorigenesis

Abstract

Regulation of protein synthesis at the level of translation initiation is fundamentally important for the control of cell proliferation under normal physiological conditions. Conversely, misregulation of protein synthesis is emerging as a major contributory factor in cancer development. Most bulk protein synthesis is initiated via recognition of the mRNA 5' cap and subsequent recognition of the initiator AUG codon by a directional scanning mechanism. However, several key regulators of tumour development are translated by a cap-independent pathway. Here we review eukaryotic translation initiation, its regulation and the ways in which this regulation can break down during tumorigenesis. TRANSLATION RATES AND GROWTH CONTROLCell growth and proliferation rates depend critically upon the rate of protein synthesis. Normal cells that are able to proliferate generally do so transiently in response to appropriate extracellular cues. Withdrawal of these growth stimuli leads to cell cycle exit associated with a marked decrease in protein synthesis. In mammalian fibroblasts, inhibiting overall protein translation by 50% is sufficient to prevent the onset of DNA replication following mitogenic stimulation. Consequently there exists a critical threshold level of total protein synthesis, which must be exceeded in order to commit each cell to a round of replication. This has been interpreted as a requirement to accumulate one or more unstable protein(s) to a predetermined level. The G1 cyclins have emerged as prime candidates for this class of regulatory proteins (reviewed in Zetterberg et al, 1995).The rate of synthesis of any given protein is determined primarily by the level of translation initiation. In mammalian cells, this is a complex process that requires collaboration between multiple eukaryotic initiation factors (eIFs: reviewed in Pestova et al, 2001). In brief, a ternary complex is formed between eIF2, GTP and the initiator methionyl-tRNA (met-tRNAi), while free 40S ribosomal subunits are bound to eIF3, a large, multi-subunit, initiation factor. Free 60S ribosomal units are similarly bound to the monomeric eIF6. Together, eIF3 and eIF6 prevent premature association of the 60S and 40S ribosomal subunits. The ternary complex is transferred to eIF3/40S along with eIF1 and eIF1A, to form a 43S pre-initiation complex. eIF3 can now bind to the eIF4F complex, which is associated with the mRNA, thus linking the 40S ribosome to the mRNA and generating the 48S pre-initiation complex (Figure 1). eIF4F itself consists of three components: eIF4G, eIF4E, and eIF4A. eIF4G binds eIF3 and acts as a scaffold for eIF4E and eIF4A. eIF4E recognises and binds the 5' mRNA cap structure while the RNAdependent ATPase eIF4A is thought to unwind secondary structure in the 5' untranslated region (UTR). eIF4B is an additional factor that may stimulate the eIF4A helicase activity and promote RNA binding. The poly(A) tail of the mRNA interacts with poly(A) binding protein (PABP), which in turn has a binding site on eIF4G allowing the mRNA to circ...

Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells

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Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

“…S6K is a Ser/Thr kinase involved in protein translation and cell growth. Excessive, dysregulated protein translation is important in several cancers and premalignant conditions (Watkins and Norbury, 2002;Brugarolas and Kaelin, 2004).…”

An oncogenic role of eIF3e/INT6 in human breast cancer

“…Deregulation of translation initiation can lead to oncogenic transformation and can support cancer growth, suggesting that targeting translation may be a valuable therapeutic approach (Thumma and Kratzke, 2007;Wendel et al, 2007;Mavrakis and Wendel, 2008). Protein synthesis is controlled by multiple translation initiation factors (eIFs), many of which have been implicated in tumorigenesis (Watkins and Norbury, 2002;Dong and Zhang, 2006). Nonetheless, despite numerous studies of the expression of eIFs in human cancers, a detailed picture of how deregulation of eIF function might modulate the quality of translation in such a way as to contribute to tumor progression is currently lacking.…”