Downstream control of upstream open reading frames
- Matthew S. Sachs1,2,6 and
- Adam P. Geballe3,4,5
- 1 Department of Environmental and Biomolecular Systems, Oregon Health and Science University, Beaverton, Oregon 97006, USA;
- 2 Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon 97201, USA;
- 3 Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- 4 Department of Microbiology and Department of Medicine, University of Washington, Seattle, Washington 98115, USA
This extract was created in the absence of an 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.
Unexpected role for the 3′UTR in a uORF regulatory mechanism
The observation that a large number of genes involved in cellular growth regulation, including the Her-2 oncogene, express mRNAs with uORFs led to speculations that uORF-mediated regulatory mechanisms might be important to prevent uncontrolled cell growth. The Her-2 gene is amplified and the protein is overexpressed in a variety of cancers, including 20%–30% of breast cancers. In such cases, the overexpression of Her-2 contributes to the malignant phenotype and therapies directed against Her-2 are useful for treating these tumors (for review, see Rabindran 2005). Thus, understanding how Her-2 expression is controlled is of considerable clinical importance.
Previous studies had revealed that the well-conserved uORF in Her-2 controlled its expression at the level of translation (Child et al. 1999a, b). When fused to a reporter gene, the uORF inhibits downstream translation in multiple cell types. …
