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...

Six cynomolgus monkeys (Macaca fascicularis) were trained to associate visual stimuli with the delivery of various amounts of food reward. The animals had to choose correctly between pairs of stimuli drawn from a population of 16. Four of these stimuli were associated with 0 reward pellets, four with 1 pellet, four with 2 pellets and four with 4 pellets. Mediodorsal thalamic lesions including the medial part of the mediodorsal nucleus, similar to those which are frequently seen in Korsakoff amnesia, produced a severe impairment in this task. The impairment was seen both in memory for the quantity of reward, as expressed in choices between 1‐pellet and 2‐pellet stimuli or choices between 2‐pellet and 4‐pellet stimuli, and also in memory for the qualitative absence or presence of reward, as expressed in choices between 0‐pellet and 1‐pellet stimuli. The deficit in this task establishes that mediodorsal thalamic lesions in monkeys can impair long‐term memory tasks, in addition to their known effects on several short‐term memory tasks. The contrast between the present results and those of previous experiments on visual long‐term memory in the monkey following mediodorsal thalamic lesions can be related to similar contrasts in studies of lesions in the amygdala, suggesting that the functions of these two structures are related.

The Int-6 gene is a site of mouse mammary tumour virus (MMTV) integration in murine tumours and INT6 protein has been identified independently as a subunit (eIF3e) of the eukaryotic translation initiation factor eIF3. In addition, the protein can interact with two other multi-subunit complexes: the COP9 signalosome (CSN) and the proteasome. The role of INT6 in tumourigenesis is nonetheless currently unclear. Here, using immunofluorescence microscopy, we show that eIF3e/INT6 is localized in part to the nucleus, while other eIF3 components are cytoplasmic. Primary human fibroblasts, but not their transformed counterparts, showed reduced nuclear INT6 staining in some cells, and this reduction was maximal in early S phase. This variation in eIF3e/INT6 may indicate regulated shuttling between cellular compartments and would be consistent with the presence of a nuclear export signal as well as a nuclear localization signal in the protein sequence. Loss of regulation of eIF3e/INT6 redistribution may therefore be a significant feature of malignancy in human cells.

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.

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