The chicken c-Jun 5′ untranslated region directs translation by internal initiation

Sehgal, Anil; Briggs, Joe; Rinehart-Kim, Janet; Basso, Johnny; Bos, Timothy J.

doi:10.1038/sj.onc.1203601

Cited by 25 publications

(22 citation statements)

References 72 publications

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“…Although the precise effects of eIF4E phosphorylation on translational efficiency of specific mRNAs have not been elucidated in cardiac muscle, we have shown in previous studies that eIF4E phosphorylation is increased in response to pressure overload hypertrophy [7,29]. Further evidence indicates that the mRNAs coding for MDM2, c-myc, c-jun, and FGF-2 contain Internal Ribosome Entry Sites (IRES), which are elements in the 5′-UTR that direct translational initiation independent of the 7 mGppp cap [30][31][32][33]. The presence of an IRES could target specific mRNAs for translation in response to a growth stimulus b facilitating capindependent initiation However, the physiological relevance of IRES elements as a mechanism of translational initiation is controversial [34].…”

Section: Discussionmentioning

confidence: 99%

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

Spruill¹,

Baicu²,

Zile³

et al. 2008

Journal of Molecular and Cellular Cardiology

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During pressure overload hypertrophy, selective changes in cardiac gene expression occur that regulate growth and modify the structural and functional properties of the myocardium. To determine the role of translational mechanisms, a murine model of transverse aortic constriction was used to screen a set of specified mRNAs for changes in translational activity by measuring incorporation into polysomes in response to acute pressure overload. Candidate mRNAs were selected on the basis of two main criteria: 1) the 5′-untranslated region of the mRNA contains an excessive amount of secondary structure (ΔG < −50 kCal/mol), which is postulated to regulate efficiency of translation, and 2) the protein product has been implicated in the regulation of cardiac hypertrophy. After 24 hours of transverse aortic constriction, homogenates derived from the left ventricle were layered onto 15%-50% linear sucrose gradients and resolved into monosome fractions (messenger ribonucleoprotein particles) and polysome fractions by density gradient ultracentrifugation. The levels of mRNA in each fraction were quantified by real-time RT-PCR. The screen revealed that pressure overload increased translational activity of 6 candidate mRNAs as determined by a significant increase in the percentage of total mRNA incorporated into the polysome fractions. The mRNAs code for several functional classes of proteins linked to cardiac hypertrophy: the transcription factors c-myc, c-jun and MEF2D, growth factors VEGF and FGF-2, and the E3 ubiquitin ligase MDM2. These studies demonstrate that acute pressure overload alters cardiac gene expression by mechanisms that selectively regulate translational activity of specific mRNAs.

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Section: Discussionmentioning

confidence: 99%

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

Spruill¹,

Baicu²,

Zile³

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…The JunD 5Ј-UTR Alters the Ratio of JunD-FL and ⌬JunD Expression-The 5Ј-UTR of the JunD mRNA is a long (120 and 138 nucleotides in rodent and human, respectively) G/C-rich sequence that is predicted to have a low free energy of folding (21). Both the rat and human 5Ј-UTRs from the mRNA 5Ј cap to the S1 AUG codon were analyzed using mfold software (27,28).…”

Section: Resultsmentioning

confidence: 99%

“…To inhibit cap-dependent translation, a synthetic hairpin sequence was placed upstream of the Renilla luciferase ORF in the dicistronic constructs. This strategy was shown previously to inhibit translation of the cap-dependent 5Ј-ORF but had no effect or even increased expression of the 3Ј-ORF when an IRES was present (21). Dicistronic vectors with or without a synthetic hairpin were transfected into CHO cells.…”

Section: Mutation Of Multiple Upstream Start Codons Increase ⌬Jund Exmentioning

confidence: 99%

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Translational Regulation of the JunD Messenger RNA

Short

Pfarr

2002

Journal of Biological Chemistry

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“…Such genes, having at least 3 CGG repeats within their IRES motifs, include previously mentioned FMR1 gene, jun proto-oncogene (JUN), ornithine decarboxylase 1 (ODC1), B-cell CLL/lymphoma 2 (BCL2), and BCL2-associated athanogene (BAG1). [64][65][66][67][68] Since it was discovered that hypoxic conditions activate the Hh-Gli pathway, and it is already known that several genes are being translated under the hypoxia by IRES-dependent mechanism, we wanted to explore if the putative PTCH1b 5'UTR IRES can be activated by oxygen deprivation condition. 42,69 The increased activity of putative IRES element within the 5'UTR of PTCH1b has been observed in transfected MCF7 cells after exposure to strong hypoxic conditions, while in HEK 293T hypoxia did not increase, in fact decreased, the activity of PTCH1b IRES element.…”

Section: Discussionmentioning

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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The chicken c-Jun 5′ untranslated region directs translation by internal initiation

Cited by 25 publications

References 72 publications

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

Translational Regulation of the JunD Messenger RNA

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

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