Tiny but mighty: Diverse functions of uORFs that regulate gene expression

Upstream open reading frames (uORFs) are critical cis-acting regulators of downstream gene expression. Specifically, uORFs regulate translation by disrupting translation initiation or mediating mRNA decay. We herein summarize the effects of several uORFs that regulate gene expression in microbes to illustrate the detailed mechanisms mediating uORF functions. Microbes are ideal for uORF studies because of their prompt responses to stimuli. Recent studies revealed uORFs are ubiquitous in higher eukaryotes. Moreover, they influence various physiological processes in mammalian cells by regulating gene expression, mostly at the translational level. Research conducted using rapidly evolving methods for ribosome profiling combined with protein analyses and computational annotations showed that uORFs in mammalian cells control gene expression similar to microbial uORFs, but they also have unique tumorigenesis-related roles because of their protein-encoding capacities. We briefly introduce cutting-edge research findings regarding uORFs in mammalian cells.