Downstream control of upstream open reading frames

Abstract

Studies over the past two decades have uncovered a surprising variety of genetic regulatory mechanisms mediated by upstream AUG (uAUG) codons and their associated upstream open reading frames (uORFs) (Lovett and Rogers 1996; Geballe and Sachs 2000; Morris and Geballe 2000; Dever 2002; Vilela and McCarthy 2003). As illustrated by an intriguing report by Mehta et al. (2006) in this issue of Genes & Development, we still have much to learn about the array of cis-acting sequences, trans-acting factors, and specific mechanisms that act with uORFs to regulate protein synthesis. Mehta et al. discovered that sequences in the 3′UTR of the Her-2 oncogene overcome the negative impact of the uORF on gene expression in some types of tumor cells. In this perspective, we provide a current view of uORF functions and regulatory mechanisms, highlighting the implications of the results of Mehta et al. (2006) for understanding ubiquitous but still-mysterious events occurring during translation and implications for tumor cell biology. © 2006 by Cold Spring Harbor Laboratory Press.