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Expression of human UPF1 is regulated by a cap-independent translation initiation mechanism

2017-05-08Conference object Restricted access
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dc.contributor.authorLacerda, Rafaela
dc.contributor.authorMenezes, Juliane
dc.contributor.authorRomão, Luísa
dc.date.accessioned2018-03-02T17:11:58Z
dc.date.embargo2025-12-31
dc.date.issued2017-05-08
dc.description.abstractGene expression comprises several intertwined steps. Translation initiation, which, under normal circumstances, is mostly cap-dependent, can also occur via a cap-independent mechanism, which drives protein synthesis under stress conditions impairing canonical translation initiation. Human up-frameshift 1 (UPF1) is a key-protein involved in nonsense-mediated mRNA decay, telomere replication and homeostasis, and cell cycle progression. These crucial UPF1 functions suggest its tight gene expression regulation. To test whether UPF1 5’ untranslated region (5’UTR) mediates cap-independent translation, we cloned the UPF1 5’UTR in a bicistronic luciferase vector upstream the downstream cistron (Firefly luciferase [FLuc]), and transfected cervical and colorectal cancer cell lines with this construct. We observed a significant increase in FLuc expression levels compared to those from Renilla luciferase (upstream cistron) in cells transfected with the UPF1 5’UTR-containing constructs compared to those transfected with the empty transcript. To find which sequence segments are required for mediating cap-independent translation, we performed a deletional and mutational analysis of the sequence and verified that cap-independent translation was ceased when the first 100 nucleotides, or the last 125, were absent or altered. Also, such activity is maintained under canonical translation initiation-impairing conditions, such as hypoxia or endoplasmic reticulum stress. We also produced in vitro cap-lacking monocistronic UPF1 5’UTR-containing transcripts and observed a significant increase in relative FLuc expression levels in cells transfected with them. These results indicate that UPF1 5’UTR mediates cap-independent translation initiation. Understanding this mechanism and its biological relevance might provide tools for developing new therapies for UPF1 deregulation-associated diseases, such as cancer.pt_PT
dc.description.sponsorshipFCTpt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/5146
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.subjectExpression of human UPF1pt_PT
dc.subjectExpressão Génicapt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.titleExpression of human UPF1 is regulated by a cap-independent translation initiation mechanismpt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlaceLisboa, Portugalpt_PT
oaire.citation.title2º Dia do Jovem Investigador do Instituto Nacional de Saúde Doutor Ricardo Jorge, 8 maio 2017pt_PT
rcaap.embargofctOs resultados ainda não foram publicadospt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typeconferenceObjectpt_PT

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