Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/2705 |
Resumo: | Erythropoietin (EPO) is a key mediator hormone for hypoxic induction of erythropoiesis that also plays important nonhematopoietic functions. It has been shown that EPO gene expression regulation occurs at different levels, including transcription and mRNA stabilization. In this report, we show that expression of EPO is also regulated at the translational level by an upstream open reading frame (uORF) of 14 codons. As judged by comparisons of protein and mRNA levels, the uORF acts as a cis-acting element that represses translation of the main EPO ORF in unstressed HEK293, HepG2, and HeLa cells. However, in response to hypoxia, this repression is significantly released, specifically in HeLa cells, through a mechanism that involves processive scanning of ribosomes from the 5' end of the EPO transcript and enhanced ribosome bypass of the uORF. In addition, we demonstrate that in HeLa cells, hypoxia induces the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) concomitantly with a significant increase of EPO protein synthesis. These findings provide a framework for understanding that production of high levels of EPO induced by hypoxia also involves regulation at the translational level. |
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Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxiaeIF2αErythropoietin (EPO)HypoxiaPhosphorylationTranslational RegulationUpstream Open Reading Frame (uORF)RNADoenças GenéticasErythropoietin (EPO) is a key mediator hormone for hypoxic induction of erythropoiesis that also plays important nonhematopoietic functions. It has been shown that EPO gene expression regulation occurs at different levels, including transcription and mRNA stabilization. In this report, we show that expression of EPO is also regulated at the translational level by an upstream open reading frame (uORF) of 14 codons. As judged by comparisons of protein and mRNA levels, the uORF acts as a cis-acting element that represses translation of the main EPO ORF in unstressed HEK293, HepG2, and HeLa cells. However, in response to hypoxia, this repression is significantly released, specifically in HeLa cells, through a mechanism that involves processive scanning of ribosomes from the 5' end of the EPO transcript and enhanced ribosome bypass of the uORF. In addition, we demonstrate that in HeLa cells, hypoxia induces the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) concomitantly with a significant increase of EPO protein synthesis. These findings provide a framework for understanding that production of high levels of EPO induced by hypoxia also involves regulation at the translational level.FCTCold Spring Harbor Laboratory Press/ RNA SocietyRepositório Científico do Instituto Nacional de SaúdeBarbosa, CristinaRomão, Luísa2015-01-29T12:28:13Z2014-03-192014-03-19T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/2705engRNA. 2014 May;20(5):594-608. doi: 10.1261/rna.040915.113. Epub 2014 Mar 191355-838210.1261/rna.040915.113info:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:39:27Zoai:repositorio.insa.pt:10400.18/2705Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:37:43.579115Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia |
title |
Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia |
spellingShingle |
Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia Barbosa, Cristina eIF2α Erythropoietin (EPO) Hypoxia Phosphorylation Translational Regulation Upstream Open Reading Frame (uORF) RNA Doenças Genéticas |
title_short |
Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia |
title_full |
Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia |
title_fullStr |
Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia |
title_full_unstemmed |
Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia |
title_sort |
Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia |
author |
Barbosa, Cristina |
author_facet |
Barbosa, Cristina Romão, Luísa |
author_role |
author |
author2 |
Romão, Luísa |
author2_role |
author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Barbosa, Cristina Romão, Luísa |
dc.subject.por.fl_str_mv |
eIF2α Erythropoietin (EPO) Hypoxia Phosphorylation Translational Regulation Upstream Open Reading Frame (uORF) RNA Doenças Genéticas |
topic |
eIF2α Erythropoietin (EPO) Hypoxia Phosphorylation Translational Regulation Upstream Open Reading Frame (uORF) RNA Doenças Genéticas |
description |
Erythropoietin (EPO) is a key mediator hormone for hypoxic induction of erythropoiesis that also plays important nonhematopoietic functions. It has been shown that EPO gene expression regulation occurs at different levels, including transcription and mRNA stabilization. In this report, we show that expression of EPO is also regulated at the translational level by an upstream open reading frame (uORF) of 14 codons. As judged by comparisons of protein and mRNA levels, the uORF acts as a cis-acting element that represses translation of the main EPO ORF in unstressed HEK293, HepG2, and HeLa cells. However, in response to hypoxia, this repression is significantly released, specifically in HeLa cells, through a mechanism that involves processive scanning of ribosomes from the 5' end of the EPO transcript and enhanced ribosome bypass of the uORF. In addition, we demonstrate that in HeLa cells, hypoxia induces the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) concomitantly with a significant increase of EPO protein synthesis. These findings provide a framework for understanding that production of high levels of EPO induced by hypoxia also involves regulation at the translational level. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014-03-19 2014-03-19T00:00:00Z 2015-01-29T12:28:13Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/2705 |
url |
http://hdl.handle.net/10400.18/2705 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
RNA. 2014 May;20(5):594-608. doi: 10.1261/rna.040915.113. Epub 2014 Mar 19 1355-8382 10.1261/rna.040915.113 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Cold Spring Harbor Laboratory Press/ RNA Society |
publisher.none.fl_str_mv |
Cold Spring Harbor Laboratory Press/ RNA Society |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799132112511565824 |