6 Translational Control Mediated by Upstream AUG Codons

Abstract

A commonly held, although not wholly accurate conception of eukaryotic messenger RNA structure envisions one major open reading frame (ORF) encoding a single polypeptide product. Flanking the ORF are sequences that may regulate properties such as the stability, subcellular distribution, or translational efficiency of the mRNA. The RNA sequence between the methyl guanosine cap and the initiation codon of the ORF typically consists of 20–100 nucleotides (Kozak 1987a) and is conventionally known as the 5′ -untranslated region (5′ UTR), even though this term is a misnomer when applied to transcript leader sequences containing upstream AUG (uAUG) codons that may function as translation initiation sites.

According to the “scanning model” of eukaryotic translation (Kozak 1989), the 40S ribosomal subunit with its associated factors engages the mRNA at or near the cap and then scans in a 3′ direction. Upon encountering the first initiation codon, the 60S subunit joins the 40S sub-unit to form a complete 80S ribosome, and polypeptide synthesis commences. This model predicts that sequence elements within 5′ UTRs have the potential to control the access of ribosomes to the downstream coding ORF. Indeed, studies of genes from many systems have revealed a variety of regulatory elements within 5′ UTRs. This chapter reviews our current understanding of the regulatory effects of uAUG codons and associated upstream ORFs (uORFs). Although the scanning model provides a useful conceptual framework for considering the effects of uAUG codons and uORFs, the model remains unproven, and alternative mechanisms are clearly involved in translation of...