Before It Gets Started: Regulating Translation at the 5′ UTR

Araújo, Patrícia Rosa de; Yoon, Kihoon; Ko, Daijin; Smith, Andrew D.; Qiao, Mu; Suresh, Uthra; Burns, Suzanne Perea; Penalva, Luiz O. F.

doi:10.1155/2012/475731

Cited by 224 publications

(207 citation statements)

References 65 publications

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“…S1). The region of 30-50 nt downstream from the 5 ′ cap is known to be bound by a 40S ribosomal subunit during formation of the 43S pre-initiation complex (Araujo et al 2012), and this process initiates capdependent gene translation. Recently published studies suggest that miRNAs repress gene translation by impairing the function of the pre-initiation complex (Meijer et al 2013;Ricci et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Many previous studies have shown that the 5 ′ UTR performs an important regulatory function in posttranscriptional processes (Davuluri et al 2000;Pickering and Willis 2005;Ringnér and Krogh 2005;Araujo et al 2012). First, the 5 ′ UTR contains several regulatory elements, such as binding sites for RNA binding proteins (RBPs), upstream open reading frames (uORFs), and upstream start codons (uAUGs), which have a great impact on the regulation of translation (Araujo et al 2012). Second, the mRNA secondary structure of the 5 ′ UTR has been recognized as a major feature that regulates gene translation (Pickering and Willis 2005).…”

Section: Thementioning

confidence: 99%

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The role of RNA structure at 5′ untranslated region in microRNA-mediated gene regulation

Xie

et al. 2014

RNA

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Recent studies have suggested that the secondary structure of the 5 ′ untranslated region (5 ′ UTR) of messenger RNA (mRNA) is important for microRNA (miRNA)-mediated gene regulation in humans. mRNAs that are targeted by miRNA tend to have a higher degree of local secondary structure in their 5 ′ UTR; however, the general role of the 5 ′ UTR in miRNA-mediated gene regulation remains unknown. We systematically surveyed the secondary structure of 5 ′ UTRs in both plant and animal species and found a universal trend of increased mRNA stability near the 5 ′ cap in mRNAs that are regulated by miRNA in animals, but not in plants. Intra-genome comparison showed that gene expression level, GC content of the 5 ′ UTR, number of miRNA target sites, and 5 ′ UTR length may influence mRNA structure near the 5 ′ cap. Our results suggest that the 5 ′ UTR secondary structure performs multiple functions in regulating post-transcriptional processes. Although the local structure immediately upstream of the start codon is involved in translation initiation, RNA structure near the 5 ′ cap site, rather than the structure of the full-length 5 ′ UTR sequences, plays an important role in miRNA-mediated gene regulation.

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Section: Discussionmentioning

confidence: 99%

Section: Thementioning

confidence: 99%

The role of RNA structure at 5′ untranslated region in microRNA-mediated gene regulation

Xie

et al. 2014

RNA

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“…[25][26][27] The 5'UTRs can differ in length, nucleotide content, secondary structures, and the presence of different functional elements. 28 The main regulatory elements in 5'UTRs are secondary structures, including internal ribosome entry sites (IRESes), upstream open reading frames (uORFs) and upstream AUG codons (uAUGs), as well as binding sites for RNA-binding proteins. 29 These cisregulatory elements can affect the stability or translational efficiency of mRNAs, resulting in a rapid alteration of protein level in response to internal and external stimuli, without the need for new mRNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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Inga (2015) Regulation of human PTCH1b expression by different 5' untranslated region cis-regulatory elements, RNA Biology, 12:3, 290-304, DOI: 10.1080/15476286.2015 PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin syndrome, a disorder characterized by developmental abnormalities and tumor susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 haploinsufficiency, suggests that fine-tuning systems of protein patched homolog 1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' untranslated region (5'UTR) in protein expression, our aim was to thoroughly explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG) n polymorphism was the main potential regulatory element studied so far but with inconsistent results and no clear association between repeat number and disease risk. Using luciferase reporter constructs in human cell lines here we show that the number of CGG repeats has no strong impact on gene expression, both at mRNA and protein levels. We observed variability in the length of 5'UTR and changes in abundance of the associated transcripts after pathway activation. We show that upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal ribosome entry site (IRES) observed using different approaches and mapped in the region comprising the CGG repeats, would counteract the effect of the uAUGs and enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured hypoxia was observed by polysomal profiling and Western blot analyses. All our results point to an exceptionally complex and so far unexplored role of 5'UTR PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling pathway.

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“…Interestingly, uORF are important regulators of translation, particularly in response to nutritional and metabolic stress (80). The OPN-5 uORF may therefore serve to regulate the translational efficiency of the OPN-5 protein under certain metabolic conditions.…”

Section: Osteopontin Splice Variantsevidence For Association With Spementioning

confidence: 99%

Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation

Viloria

Hill

2016

Biomolecular Concepts

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Matricellular proteins influence wide-ranging fundamental cellular processes including cell adhesion, migration, growth and differentiation. They achieve this both through interactions with cell surface receptors and regulation of the matrix environment. Many matricellular proteins are also associated with diverse clinical disorders including cancer and diabetes. Alternative splicing is a precisely regulated process that can produce multiple isoforms with variable functions from a single gene. To date, the expression of alternate transcripts for the matricellular family has been reported for only a handful of genes. Here we analyse the evidence for alternative splicing across the matricellular family including the secreted protein acidic and rich in cysteine (SPARC), thrombospondin, tenascin and CCN families. We find that matricellular proteins have double the average number of splice variants per gene, and discuss the types of domain affected by splicing in matricellular proteins. We also review the clinical significance of alternative splicing for three specific matricellular proteins that have been relatively well characterised: osteopontin (OPN), tenascin-C (TNC) and periostin. Embracing the complexity of matricellular splice variants will be important for understanding the sometimes contradictory function of these powerful regulatory proteins, and for their effective clinical application as biomarkers and therapeutic targets.

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Before It Gets Started: Regulating Translation at the 5′ UTR

Cited by 224 publications

References 65 publications

The role of RNA structure at 5′ untranslated region in microRNA-mediated gene regulation

The role of RNA structure at 5′ untranslated region in microRNA-mediated gene regulation

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation

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