Cap-Independent Translation of Picornavirus RN As:
Structure and Function of the Internal Ribosomal Entry Site

Jang, Sung Key; Pestova, Tatyana V.; Hellen, Christopher U.T.; Witherell, Gary W.; Wimmer, Eckard

doi:10.1159/000468766

Cited by 191 publications

(129 citation statements)

References 24 publications

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“…The IRES-dependent translation was initially discovered in the viral gene translation of picornaviruses in host cells (40). The mRNAs of these viruses are naturally uncapped at their 5 ¶-end.…”

Section: Discussionmentioning

confidence: 99%

Incorporation of an Internal Ribosome Entry Site–Dependent Mechanism in Arsenic-Induced GADD45α Expression

et al. 2007

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We have previously shown that trivalent arsenic (arsenite, As 3+ ) is able to induce GADD45A expression in human bronchial epithelial cells through activation of c-Jun NH 2 -terminal kinase and nucleolin-dependent mRNA stabilization. In the present report, we show that As 3+ is capable of inducing translation of the GADD45A protein through a cap-independent, or rather, an internal ribosome entry site (IRES)-dependent mechanism. In growth-arrested cells, As 3+ elevated the GADD45A protein level in a dose-and time-dependent manner which did not correlate with the GADD45A mRNA expression. Pretreatment of the cells with rapamycin, an inhibitor for the cap-dependent translation machinery through the suppression of mTOR and p70S6 kinase, failed to affect the induction of the GADD45A protein induced by As 3+ . Sequence analysis revealed a potential IRES element in the 5 ¶-untranslated region of the GADD45A mRNA. This IRES element in the 5 ¶-untranslated region of the GADD45A mRNA is functional in mediating As 3+ -induced translation of the GADD45A protein in a dicistronic reporter gene activity assay. Immunoprecipitation and proteomic studies suggest that As 3+ impairs the assembly of the cap-dependent initiating complex for general protein translation but increases the association of human elongation factor 2 and human heterogeneous nuclear ribonucleoprotin with this complex. Thus, these results suggest that in growth-arrested cells, As 3+ is still capable of inducing GADD45A expression through an IRES-dependent translational regulation. [Cancer Res 2007;67(13):6146-54]

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Section: Discussionmentioning

confidence: 99%

Incorporation of an Internal Ribosome Entry Site–Dependent Mechanism in Arsenic-Induced GADD45α Expression

et al. 2007

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“…Picornaviral mRNA, like many RNA viruses, is uncapped or lacks the 5' terminal m 7 GpppN cap structure found in cellular mRNAs (Belsham, 2009). Instead, picornaviruses and other IRES translating viruses contain a small, virusencoded peptide or VPg (Jang, et al, 1990). The discovery of IRES elements across a variety of viruses also identified distinct structural and functional differences amongst them, leading to the implementation of an IRES classification scheme.…”

Section: Classification Of Viral Iressmentioning

confidence: 99%

Viral Replication Strategies: Manipulation of ER Stress Response Pathways and Promotion of IRES-Dependent Translation

Hanson¹,

Zhang²,

Hemida³

et al. 2013

Viral Replication

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“…IRES functionality is based on secondary or tertiary structure rather than primary sequence and the predicted structure of PRNP exon 2 generated using Mfold software (www.bioinfo.rpi.edu/applications/mfold; Zuker, 2003) is shown to exhibit a stem and loop appearance ( Supplementary Fig. S1), typical of a functional IRES (Jang et al, 1990). Interestingly, the mRNA encoding Ure2 protein, which is altered from the yeast prion form Ure2p, has been found to contain an IRES within the ORF (Komar et al, 2003).…”

Section: Scrapie-negativementioning

confidence: 99%

Ovine PRNP untranslated region and promoter haplotype diversity

Saunders

Cawthraw

Mountjoy

et al. 2009

Journal of General Virology

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The diversity and possible contribution of non-coding regions of the prion protein (PrP) gene (PRNP) to transmissible spongiform encephalopathy susceptibility and PrP regulation are not fully known. This study defined ten ovine PRNP promoters and five untranslated region (UTR) haplotypes found in atypical and classical scrapie cases and healthy control sheep. A greater diversity of promoter and UTR haplotypes was observed in conjunction with the ARQ PrP allele (seven promoter and four UTR haplotypes), while it was observed that the other alleles were linked with a limited number of haplotypes, such as ARR, found to be linked to only two promoter and one UTR haplotypes. In silico analysis identified potential transcription factor binding sites that differed in the promoter haplotype variants. Furthermore, a 59 UTR internal ribosome entry site motif was identified in exon 2 and highlights a possible role for this exon in regulating PrP expression at the translational level.Scrapie is a member of the transmissible spongiform encephalopathy (TSE) family of diseases, whose natural hosts are sheep and goats. TSEs are degenerative disorders of the nervous system and are invariably fatal. Irrespective of whether these diseases are acquired, inherited or of idiopathic origin, the prion protein (PrP) plays a central role (Prusiner, 1998).The PRNP gene codes for the ovine PrP, is over 20 kb long and contains three exons separated by two introns of 2421 and 14031 bp (Lee et al., 1998). The 768 bp coding region or open reading frame (ORF) of PrP is contained entirely within exon 3. The 59 untranslated region (UTR) consists of exon 1, exon 2 and bases 1-10 of exon 3 and the 39 UTR (bases 779-4028) of exon 3 (Fig. 1).Polymorphisms within the PRNP ORF are known to be associated with susceptibility and resistance to classical and atypical scrapie in sheep (Goldmann et al., 1994;Benestad et al., 2003;Moum et al., 2005 (shortened to ARQ when omitting the 141 codon). This allele, plus those generated through the substitution of one of its amino acids, make up the six most common ovine PrP alleles, namely ARQ, VRQ, AHQ, ARR and ARH, which all have leucine at position 141, and AF 141 RQ, which has phenylalanine at this position.Other regions of PRNP could also influence susceptibility, either independently or in synergy with the coding region, and may prove beneficial in future breeding plans, particularly in rare breeds, to maximize genetic diversity in the national flock whilst maintaining scrapie resistance (Dawson et al., 2008). For example, polymorphisms in the PRNP promoter region could destroy or create a transcription factor binding site (TFBS) that in turn leads to the down-or upregulation of PrP and influences disease susceptibility or incubation period. The mechanism by which the 39 UTR region of PRNP could affect scrapie susceptibility and resistance is not known; however, Goldmann et al. (1999) demonstrated that the length of the 39 UTR in mRNA can affect PrP expression levels. In general, the 39 UTR can be involved in ...

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Cap-Independent Translation of Picornavirus RN As: Structure and Function of the Internal Ribosomal Entry Site

Cited by 191 publications

References 24 publications

Incorporation of an Internal Ribosome Entry Site–Dependent Mechanism in Arsenic-Induced GADD45α Expression

Incorporation of an Internal Ribosome Entry Site–Dependent Mechanism in Arsenic-Induced GADD45α Expression

Viral Replication Strategies: Manipulation of ER Stress Response Pathways and Promotion of IRES-Dependent Translation

Ovine PRNP untranslated region and promoter haplotype diversity

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