Control of gene expression is achieved at various levels. Translational control becomes crucial in the absence of transcription, such as occurs in early developmental stages. One of the initiating events in translation is that the 40S subunit of the ribosome binds the mRNA at the 5′-cap structure and scans the 5′-untranslated region (5′-UTR) for AUG initiation codons. AUG codons upstream of the main open reading frame can induce formation of a translation-competent ribosome that may translate and (i) terminate and re-initiate, (ii) terminate and leave the mRNA, resulting in down-regulation of translation of the main open reading frame, or (iii) synthesize an N-terminally extended protein. In the present review we discuss how upstream AUGs can control the expression of the main open reading frame, and a comparison is made with other elements in the 5′-UTR that control mRNA translation, such as hairpins and internal ribosome entry sites. Recent data indicate the flexibility of controlling translation initiation, and how the mode of ribosome entry on the mRNA as well as the elements in the 5′-UTR can accurately regulate the amount of protein synthesized from a specific mRNA.

Abbreviations used: AAP, arginine attenuator peptide; AdoMetDC, S-adenosylmethionine decarboxylase; Apaf-1, apoptotic protease activating factor; ATF4, activating transcription factor 4; CaMV, cauliflower mosaic virus; C/EBP, CCAAT/enhancer binding protein; CNP, 2′,3′-cyclic nucleotide 3-phosphodiesterase; CUGBP1, CUG repeat binding protein 1; eALAS, erythroid Δ-aminolaevulinate synthase; eIF, eukaryotic initiation factor; 4E-BP, eIF4E-binding protein; FGF, fibroblast growth factor; gpUL4, human cytomegalovirus early glycoprotein; IGF, insulin-like growth factor; IRE, iron-responsive element; IRES, internal ribosome entry site; IRP, iron-regulatory protein; NMD, nonsense-mediated decay; ODC, ornithine decarboxylase; ORF, open reading frame; PABP, poly(A)-binding protein; PDGF, platelet-derived growth factor; RARβ2, retinoic acid receptor β2; sAUG, start AUG; TfR, transferrin receptor; TGF, transforming growth factor; uAUG, upstream AUG; uORF, upstream open reading frame; UTR, untranslated region; VEGF, vascular endothelial growth factor; XIAP, X-linked inhibitor of apoptosis protein.

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Author notes


Present address and address for correspondence: School of Biomedical Sciences, Queens Medical Centre, University of Nottingham, Nottingham NG7 2UH, U.K. (e-mail