18 Translational Control by Upstream Open Reading Frames

A commonly held but not always correct 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 translational efficiency, stability, and subcellular distribution of the mRNA. The RNA sequence between the methyl guanosine cap and the initiation codon of the ORF 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 function as translation initiation sites. A large number (though a small fraction, overall) of eukaryotic mRNAs contain uAUGs in their 5′UTRs. Three potential configurations of ORFs that follow uAUG codons based on the position of their termination codons are shown in Figure 1. A nonoverlapping upstream open reading frame (uORF) results from a termination codon being in the 5′UTR. An overlapping uORF has its termination codons within the major coding ORF of the mRNA. Finally, a reading frame initiated by the uAUG codon may be in-frame with the downstream ORF and end at the same termination site. In this latter case, the resulting amino-terminal extension to the major protein product may provide additional domains that confer important auxiliary functions to the protein. The control of expression of such alternative proteins appears determined by initiation codon selection (see Chapters 5 and 12). As described in this chapter, additional control mechanisms operate to regulate expression downstream from nonoverlapping and overlapping uORFs. Other reviews that...