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Continuing discoveries of new and surprising mechanisms of gene regulation suggest that our understanding of this complex and ubiquitous biological process remains incomplete. Emerg- ing examples illustrate that many and perhaps all genes are regulated at multiple steps including transcription, posttran- scriptional processing, nuclear export and localization, stabil- ity, and translation of mature mRNA molecules. Translation itself is regulated by a diverse collection of mechanisms that act not only at the initiation step but also during elongation and termination and even after termination. Among the various cis elements in mRNAs (43) that partic- ipate in regulating translation are AUG codons within tran- script leaders (upstream AUGs (uAUGs)) and, in some cases, associated upstream open reading frames (uORFs). Based on a 1987 survey, less than 10% of eukaryotic mRNAs contain AUG codons within their transcript leader regions (often er- roneously referred to as 59 untranslated regions). However, uAUGs are conspicuously common in certain classes of genes, including two-thirds of oncogenes and many other genes in- volved in the control of cellular growth and differentiation (29, 31, 42). Despite the wealth of sequence data being generated by large-scale sequencing projects, extracting an up-to-date, comprehensive, and accurate estimate of the number of genes with uORFs is a formidable task. Only a minority of database entries are based on careful mRNA mapping data with anno- tations that identify the precise start of the transcript leader. Moreover, the use of alternative transcriptional start sites, alternative RNA processing, and alternative initiation codons complicates the determination of what exactly constitutes the transcript leader. Nonetheless, it is clear that uAUGs are not uncommon in genes with critical cellular roles, and identifying when and how they function is necessary if we are to achieve a comprehensive understanding of the interesting genes that contain these elements and of eukaryotic gene regulation in general. Some of the general principles by which uORFs participate in translational control are beginning to be understood. In this article, we first review these principles, which include the pro- cess of recognition of uORFs, regulation of reinitiation at downstream cistrons after translation of uORFs, and regula- tory effects of peptides encoded by uORFs. We then illustrate how these principles are applied by reviewing several specific examples where the roles of uORFs in translational control have been well characterized.

Upstream Open Reading Frames as Regulators of mRNA Translation