Upstream open reading frames: Molecular switches in (patho)physiology

Abstract

Conserved upstream open reading frames (uORFs) are found within many eukaryotic transcripts and are known to regulate protein translation. Evidence from genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of human diseases. A genetic mouse model has recently provided proof-of-principle support for the physiological relevance of uORF-mediated translational control in mammals. The targeted disruption of the uORF initiation codon within the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) gene resulted in deregulated C/EBPβ protein isoform expression, associated with defective liver regeneration and impaired osteoclast differentiation. The high prevalence of uORFs in the human transcriptome suggests that intensified search for mutations within 5′ RNA leader regions may reveal a multitude of alterations affecting uORFs, causing pathogenic deregulation of protein expression.

Introns in UTRs: Why we should stop ignoring them

“…Thus uORFs are prevalent, translated, and often conserved, indicating that many are functional. However, uORFs may have functions besides NMD [60,61], so the presence of a conserved uORF does not necessarily mean an mRNA is regulated by NMD. For example, it is possible that some ribosomes translating a uORF either fail to recognize the uORF termination codon or reinitiate on the main ORF downstream [62].…”

Regulation of translation by upstream translation initiation codons of surfactant protein A1 splice variants

“…Although the termination codons for these uORFs are upstream of all AUGs, the ribosomes are less likely to reinitiate translation from the uAUGs because of their proximity to the release site of the ribosome subunits from the uORFs. The distance between the termination codon in positions 84 -86 and the AUG p on the other hand may allow the reinitiation of translation by the ribosomes (95). The role of these uORFs in the regulation of SP-A1 expression is of interest for further research.…”

“…The results of these studies associate the presence of uAUGs with pathophysiology. This is further acknowledged by the identification of pathogenic mutations that introduce uAUGs in several genes (44,95). There are Ͼ509 human genes identified with single nucleotide polymorphisms that either create or delete an uORF, and some of these are related to a wide spectrum of diseases, ranging from cancer to hereditary thrombocythemia (78).…”

CCAAT enhancer-binding proteins have long boney fingers

“…How can we tie these components together? The answers follow years of effort from the Leutz laboratory [9][10][11][12][13]. The story begins with their elucidation of how translational control of C/EBPβ isoforms is regulated.…”

“…The pathway functions as a nutrient energy/redox sensor and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, transcription, and as we see here, also translation. The Leutz laboratory has recently reviewed the mechanisms how uORF regulate C/EBPβ mRNA isoform production [10]. Under the influence of mTOR activation, C/EBPβ mRNA produces more LIP and less LAP.…”