A perspective on mammalian upstream open reading frame function

Abstract

Post-transcriptional control makes a major contribution to the overall regulation of gene expression pathway. Within the cytoplasm this is mediated by a combination of regulatory RNA motifs within the 5' and 3' untranslated regions of mRNAs and their interacting protein/RNA partners. One of the most common regulatory RNA elements in mammalian transcripts (present in approximately 40% of all mRNAs) are upstream open reading frames (uORFs). However, despite the prevalence of these RNA elements how they function is not well understood. In general, they act to repress translation of the physiological ORF under control conditions, and under certain pathophysiological stresses this repression can be alleviated. It is known that re-initiation following the translation of an uORF is utilised in some situations however there are numerous alternative mechanisms that control the synthesis of a protein whose mRNA contains uORFs. Moreover, the trans-acting factors that are also involved in this process are not well defined. In this review we summarise our current understanding of this area and highlight some common features of these RNA motifs that have been discovered to date.

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

“…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). Recently this observation led to accurate regulation of ectopic protein expression (p21) with the use of small synthetic uORF, to control the ribosome flux to the primary ORF (13).…”

Mixed messages: Re-initiation factors regulate translation of animal mRNAs

“…npg Taken together, Schleich et al uncover metazoan factors which specifically regulate re-initiation downstream of uORFs with strong Kozak context in a specific cellular context. While it cannot be ruled out that DENR/MCT-1 also have more widespread and potentially indirect effects on translation, their role in re-initiation contrasts with a wellstudied response to cell stress in which initiation at uORFs and downstream re-initiation are globally coupled [3].…”

“…Protein output from the main ORF is reduced when initiation at the uORF leads to ribosomal stalling during elongation or termination, dissociation of both ribosomal subunits from the mRNA, or even degradation of the mRNA itself [3]. Further, little is known about factors that could regulate uORF effects in a sequence-specific manner.…”

“…One of the few examples is Sex lethal, which binds upstream of the main start codon and promotes initiation at a uORF [8]. Also, expression of different 5′ UTR isoforms can influence uORF regulation [3]. In some cases, a uORFencoded small peptide can interfere with translation in cis or in trans [3].…”

“…Also, expression of different 5′ UTR isoforms can influence uORF regulation [3]. In some cases, a uORFencoded small peptide can interfere with translation in cis or in trans [3]. In fact, many small ORFs in the 5′ or 3′ UTRs of mRNAs are not only translated but also give rise to detectable small peptides [9,10].…”