Control of eukaryotic protein synthesis by upstream open reading frames in the 5′-untranslated region of an mRNA

Abstract

Control of gene expression is achieved at various levels. Translational control becomes crucial in the absence of transcription, such as occurs in early developmental stages. One of the initiating events in translation is that the 40 S subunit of the ribosome binds the mRNA at the 5'-cap structure and scans the 5'-untranslated region (5'-UTR) for AUG initiation codons. AUG codons upstream of the main open reading frame can induce formation of a translation-competent ribosome that may translate and (i) terminate and re-initiate, (ii) terminate and leave the mRNA, resulting in down-regulation of translation of the main open reading frame, or (iii) synthesize an N-terminally extended protein. In the present review we discuss how upstream AUGs can control the expression of the main open reading frame, and a comparison is made with other elements in the 5'-UTR that control mRNA translation, such as hairpins and internal ribosome entry sites. Recent data indicate the flexibility of controlling translation initiation, and how the mode of ribosome entry on the mRNA as well as the elements in the 5'-UTR can accurately regulate the amount of protein synthesized from a specific mRNA.

The role of 5′ untranslated region in translational suppression of OKL38 mRNA in hepatocellular carcinoma

“…The long structured 5 0 UTRs of the HuOKL38-2a and -2b transcripts might contribute to the suppression of the OKL38 mRNAs translation, which was previously reported in BRCA1 (Pickering and Willis, 2005), MDM2, TGFb and Bcl-2 mRNAs (Willis, 1999). Conversely, RNA-binding protein such as HuR (Kullmann et al, 2002) and/or other internal initiation trans-acting factors such as hnRNPK, La-autoantigen and polypyrimidine-tract-binding protein might also interact with OKL38 mRNAs and prevent their translation (Meijer and Thomas, 2002). These proteins could be overexpressed in HCC leading to differential suppression of translation.…”

Starting the protein synthesis machine: eukaryotic translation initiation

“…We will refer in passing to major pathways of regulating initiation factor function; however, several recent review articles cover this topic more comprehensively. (4)(5)(6)(7)(8) An important alternative pathway for initiating translation, by internal ribosome entry, is also not covered here. Internal ribosome entry sites (IRES) were initially discovered in certain viral RNAs but this mode of initiation is also employed by some cellular mRNAs (see Refs.…”

Noise–mean relationship in mutated promoters

“…We repeated this analysis for mutants with a new out-of-frame ATG, but due to low numbers it was difficult to reach significant conclusions (Table 2). However, we do expect this type of mutation to be context-dependent (Meijer and Thomas 2002;Sachs and Geballe 2006).…”

“…Notably, we find that they typically contain one of two mutation types: elimination of the TATA box or addition of an out-of-frame ATG start codon (Table 1). In the latter case, the upstream ATG probably reduces burst size via nonproductive translation, although some YFP is generated from the original ATG due to ''slippage'' in translation initiation or reinitiation (Meijer and Thomas 2002;Sachs and Geballe 2006). The upstream ATG may also lower transcript levels (Yun et al 2012).…”