The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2

Hepatocyte nuclear factor 4 alpha (HNF4α) nuclear receptor is a master regulator of hepatocyte development, nutrient transport and metabolism. HNF4α is regulated both at the transcriptional and post-transcriptional levels by different mechanisms. Several kinases (PKA, PKC, AMPK) were shown to phosph...

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Autores: Vető, Borbála, Bojcsuk, Dora, Bacquet Pérez, Caroline Nicole, Kiss, Judit, Sipeki, Szabolcs, Martin, Ludovic, Buday, Laszlo, Bálint, BL., Arányi, Tamas
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:Ecuador
Institución:Universidad Regional Amazónica
Repositorio:Repositorio Universidad Regional Amazónica
OAI Identifier:oai:repositorio.ikiam.edu.ec:RD_IKIAM/156
Acceso en línea:http://repositorio.ikiam.edu.ec/jspui/handle/RD_IKIAM/156
https://doi.org/10.1371/journal.pone.0172020
Access Level:acceso abierto
Palabra clave:Alpha (HNF4α)
HNF4α
Nutrient
Metabolism
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spelling The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2Vető, BorbálaBojcsuk, DoraBacquet Pérez, Caroline NicoleKiss, JuditSipeki, SzabolcsMartin, LudovicBuday, LaszloBálint, BL.Arányi, TamasAlpha (HNF4α)HNF4αNutrientMetabolismHepatocyte nuclear factor 4 alpha (HNF4α) nuclear receptor is a master regulator of hepatocyte development, nutrient transport and metabolism. HNF4α is regulated both at the transcriptional and post-transcriptional levels by different mechanisms. Several kinases (PKA, PKC, AMPK) were shown to phosphorylate and decrease the activity of HNF4α. Activation of the ERK1/2 signalling pathway, inducing proliferation and survival, inhibits the expression of HNF4α. However, based on our previous results we hypothesized that HNF4α is also regulated at the post-transcriptional level by ERK1/2. Here we show that ERK1/2 is capable of directly phosphorylating HNF4α in vitro at several phosphorylation sites including residues previously shown to be targeted by other kinases, as well. Furthermore, we also demonstrate that phosphorylation of HNF4α leads to a reduced trans-activational capacity of the nuclear receptor in luciferase reporter gene assay. We confirm the functional relevance of these findings by demonstrating with ChIP-qPCR experiments that 30-minute activation of ERK1/2 leads to reduced chromatin binding of HNF4α. Accordingly, we have observed decreasing but not disappearing binding of HNF4α to the target genes. In addition, 24-hour activation of the pathway further decreased HNF4α chromatin binding to specific loci in ChIP-qPCR experiments, which confirms the previous reports on the decreased expression of the HNF4a gene due to ERK1/2 activation. Our data suggest that the ERK1/2 pathway plays an important role in the regulation of HNF4α-dependent hepatic gene expression.Public Library of Science2019-06-05T17:14:43Z2019-06-05T17:14:43Z2017info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfVető, B., Bojcsuk, D., Bacquet, C., Kiss, J., Sipeki, S., Martin, L., … Arányi, T. (2017). The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2. PLoS ONE, 12(2), e0172020. doi:10.1371/journal.pone.0172020http://repositorio.ikiam.edu.ec/jspui/handle/RD_IKIAM/156https://doi.org/10.1371/journal.pone.0172020enAtribución-NoComercial-SinDerivadas 3.0 Estados Unidos de Américahttp://creativecommons.org/licenses/by-nc-nd/3.0/us/info:eu-repo/semantics/openAccessreponame:Repositorio Universidad Regional Amazónicainstname:Universidad Regional Amazónicainstacron:IKIAM2022-06-04T08:02:12Zoai:repositorio.ikiam.edu.ec:RD_IKIAM/156Institucionalhttps://repositorio.ikiam.edu.ec/Universidad públicahttps://www.ikiam.edu.ec/https://repositorio.ikiam.edu.ec/oaiEcuador...opendoar:02022-06-04T08:02:12falseInstitucionalhttps://repositorio.ikiam.edu.ec/Universidad públicahttps://www.ikiam.edu.ec/https://repositorio.ikiam.edu.ec/oai.Ecuador...opendoar:02022-06-04T08:02:12Repositorio Universidad Regional Amazónica - Universidad Regional Amazónicafalse
dc.title.none.fl_str_mv The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2
title The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2
spellingShingle The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2
Vető, Borbála
Alpha (HNF4α)
HNF4α
Nutrient
Metabolism
title_short The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2
title_full The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2
title_fullStr The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2
title_full_unstemmed The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2
title_sort The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2
dc.creator.none.fl_str_mv Vető, Borbála
Bojcsuk, Dora
Bacquet Pérez, Caroline Nicole
Kiss, Judit
Sipeki, Szabolcs
Martin, Ludovic
Buday, Laszlo
Bálint, BL.
Arányi, Tamas
author Vető, Borbála
author_facet Vető, Borbála
Bojcsuk, Dora
Bacquet Pérez, Caroline Nicole
Kiss, Judit
Sipeki, Szabolcs
Martin, Ludovic
Buday, Laszlo
Bálint, BL.
Arányi, Tamas
author_role author
author2 Bojcsuk, Dora
Bacquet Pérez, Caroline Nicole
Kiss, Judit
Sipeki, Szabolcs
Martin, Ludovic
Buday, Laszlo
Bálint, BL.
Arányi, Tamas
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alpha (HNF4α)
HNF4α
Nutrient
Metabolism
topic Alpha (HNF4α)
HNF4α
Nutrient
Metabolism
description Hepatocyte nuclear factor 4 alpha (HNF4α) nuclear receptor is a master regulator of hepatocyte development, nutrient transport and metabolism. HNF4α is regulated both at the transcriptional and post-transcriptional levels by different mechanisms. Several kinases (PKA, PKC, AMPK) were shown to phosphorylate and decrease the activity of HNF4α. Activation of the ERK1/2 signalling pathway, inducing proliferation and survival, inhibits the expression of HNF4α. However, based on our previous results we hypothesized that HNF4α is also regulated at the post-transcriptional level by ERK1/2. Here we show that ERK1/2 is capable of directly phosphorylating HNF4α in vitro at several phosphorylation sites including residues previously shown to be targeted by other kinases, as well. Furthermore, we also demonstrate that phosphorylation of HNF4α leads to a reduced trans-activational capacity of the nuclear receptor in luciferase reporter gene assay. We confirm the functional relevance of these findings by demonstrating with ChIP-qPCR experiments that 30-minute activation of ERK1/2 leads to reduced chromatin binding of HNF4α. Accordingly, we have observed decreasing but not disappearing binding of HNF4α to the target genes. In addition, 24-hour activation of the pathway further decreased HNF4α chromatin binding to specific loci in ChIP-qPCR experiments, which confirms the previous reports on the decreased expression of the HNF4a gene due to ERK1/2 activation. Our data suggest that the ERK1/2 pathway plays an important role in the regulation of HNF4α-dependent hepatic gene expression.
publishDate 2017
dc.date.none.fl_str_mv 2017
2019-06-05T17:14:43Z
2019-06-05T17:14:43Z
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv Vető, B., Bojcsuk, D., Bacquet, C., Kiss, J., Sipeki, S., Martin, L., … Arányi, T. (2017). The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2. PLoS ONE, 12(2), e0172020. doi:10.1371/journal.pone.0172020
http://repositorio.ikiam.edu.ec/jspui/handle/RD_IKIAM/156
https://doi.org/10.1371/journal.pone.0172020
identifier_str_mv Vető, B., Bojcsuk, D., Bacquet, C., Kiss, J., Sipeki, S., Martin, L., … Arányi, T. (2017). The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2. PLoS ONE, 12(2), e0172020. doi:10.1371/journal.pone.0172020
url http://repositorio.ikiam.edu.ec/jspui/handle/RD_IKIAM/156
https://doi.org/10.1371/journal.pone.0172020
dc.language.none.fl_str_mv en
language_invalid_str_mv en
dc.rights.none.fl_str_mv Atribución-NoComercial-SinDerivadas 3.0 Estados Unidos de América
http://creativecommons.org/licenses/by-nc-nd/3.0/us/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Atribución-NoComercial-SinDerivadas 3.0 Estados Unidos de América
http://creativecommons.org/licenses/by-nc-nd/3.0/us/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:Repositorio Universidad Regional Amazónica
instname:Universidad Regional Amazónica
instacron:IKIAM
instname_str Universidad Regional Amazónica
instacron_str IKIAM
institution IKIAM
reponame_str Repositorio Universidad Regional Amazónica
collection Repositorio Universidad Regional Amazónica
repository.name.fl_str_mv Repositorio Universidad Regional Amazónica - Universidad Regional Amazónica
repository.mail.fl_str_mv .
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