Initiation of Protein Synthesis in Eukaryotic Cells

Abstract

It is becoming increasingly apparent that translational control plays an important role in the regulation of gene expression in eukaryotic cells. Most of the known physiological effects on translation are exerted at the level of polypeptide chain initiation. Research on initiation of translation over the past five years has yielded much new information, which can be divided into three main areas: (a) structure and function of initiation factors (including identification by sequencing studies of consensus domains and motifs) and investigation of protein-protein and protein-RNA interactions during initiation ; (b) physiological regulation of initiation factor activities and (c) identification of features in the 5' and 3' untranslated regions of messenger RNA molecules that regulate the selection of these mRNAs for translation. This review aims to assess recent progress in these three areas and to explore their interrelationships.Keywords: translation; initiation; mRNA ; review, regulation.In 1986 I published a review describing the mechanism and regulation of initiation of translation in mammalian cells 121. By that time most of the polypeptide initiation factors catalysing this process had been extensively purified and their individual activities studied in various in vitro systems. Several of them had been shown to be phosphoproteins and, in one case, eukaryotic initiation factor-2 (eIF-2), the effects of phosphorylation had been elucidated and two physiological kinases had been identified. There seemed to be a feeling in some circles that the most interesting problems in protein synthesis had been solved, and that only a few rather boring nuts and bolts awaited discovery.Over the intervening ten years there has been an explosion of research activity in this area, largely fuelled by information yielded by molecular biology and genetic techniques. Cloning of cDNAs encoding initiation factors has revealed domain structures indicative of function and potential regulatory mechanisms. Experiments exploiting the ability to elucidate and manipulate mRNA sequences have demonstrated that translational control contributes to changes in patterns of gene expression during growth, differentiation and development to an extent that would have seemed inconceivable in 1985. Such experiments have, in particular, revealed important roles for structural fea- UTR, untranslated region (in mRNA); RRM, RNA recognition motif; ORF, open reading frame; EMCV, encephalomyocarditis virus ; FMDV, foot-and-mouth disease virus ; IRES, internal ribosome entry segment ; PTB, polypyrimidine tract binding protein ; HCR, heme-controlled repressor; PKR, protein kinase activated by RNA; dsRNA, doublestranded RNA; p70ShK and p 9 0 k , 70 kDa and 90-92 kDa ribosomal protein S6 kinases ; GSK, glycogen synthase kinase ; IRE, iron-regulatory element; IRP, iron regulatory protein ; PABP, poly(A) binding protein; AMV, alfalfa mosaic virus ; CPE, cytoplasmic polyadenylation element (also known as ACE, adenylation control element); MAP, mitogenactivated protei...

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

“…Dysregulation of this process (for example by over-expression of eIF4E or eIF4G (LazarisKaratzas et al, 1990;De Benedetti and Rhoads, 1990;Fukuchi-Shimogori et al, 1997) or by mutation of the phosphorylation site in eIF2a (Donze et al, 1995) can lead to aberrant growth and oncogenic transformation. Much e ort has been devoted to understanding the means by which reversible phosphorylation of factors such as eIF2, eIF4E and the 4E-BPs controls protein synthesis (reviewed in Pain, 1996). However, rather little attention has been paid to the role of acute changes in the levels of individual initiation factors in translational control, in spite of the fact that the signi®cance of the relative amounts of key factors has been a subject for keen debate (Hershey, 1994;Rau et al, 1996).…”

“…The initiation of protein synthesis is regulated by complex interactions between a large number of protein initiation factors and RNA molecules (Pain, 1996;Merrick and Hershey, 1996). Disruption of this process can lead to transformation of cells to an oncogenic phenotype, probably as a result of aberrant expression of proteins involved in the control of cell growth or cell death .…”

The role of c-myc in cellular growth control

“…This assembly is regulated by the translation initiation factors (Pain, 1996;Sonenberg and Gingras, 1998). Translation initiation factors have long been viewed as rate-limiting in protein synthesis because they are less abundant than ribosomal components themselves and because ribosomal elongation is rarely rate-limiting (Duncan and Hershey, 1983Hershey, , 1985.…”

Functional importance of RNA interactions in selection of translation initiation codons

“…Here, we discuss basic and some proposed alternative mechanisms that may contribute to the selection of translational start sites in prokaryotes and eukaryotes with an emphasis on the influence of RNA-RNA and RNA-protein interactions. As this area of research is vast and general aspects of translation initiation have recently been reviewed (Jackson, 1996;Pain, 1996;Voorma, 1996), we shall not be comprehensive, but focus our attention on recent developments and some controversial topics. In particular, we discuss the functional role of mRNA 'consensus sequences', the significance of proposed translational enhancer elements, and possible contributions of trans-acting factors.…”