Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.

p27Kip1 (p27) is a negative regulator of proliferation and a tumor suppressor via the inhibition of cyclin-CDK activity in the nucleus. p27 is also involved in the regulation of other cellular processes, including transcription by acting as a transcriptional co-repressor. Loss of p27 expression is f...

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Autores: Jeannot, Pauline, Callot, Caroline, Baer, Romain, Duquesnes, Nicolas, Guerra, Carmen, Guillermet-Guibert, Julie, Bachs Valldeneu, Oriol, Besson, Arnaud
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/105927
Acceso en línea:https://hdl.handle.net/2445/105927
Access Level:acceso abierto
Palabra clave:Pàncrees
Cicle cel·lular
Inhibidors enzimàtics
Proteïnes quinases
Pancreas
Cell cycle
Enzyme inhibitors
Protein kinases
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spelling Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.Jeannot, PaulineCallot, CarolineBaer, RomainDuquesnes, NicolasGuerra, CarmenGuillermet-Guibert, JulieBachs Valldeneu, OriolBesson, ArnaudPàncreesCicle cel·lularInhibidors enzimàticsProteïnes quinasesPancreasCell cycleEnzyme inhibitorsProtein kinasesp27Kip1 (p27) is a negative regulator of proliferation and a tumor suppressor via the inhibition of cyclin-CDK activity in the nucleus. p27 is also involved in the regulation of other cellular processes, including transcription by acting as a transcriptional co-repressor. Loss of p27 expression is frequently observed in pancreatic adenocarcinomas in human and is associated with decreased patient survival. Similarly, in a mouse model of K-Ras-driven pancreatic cancer, loss of p27 accelerates tumor development and shortens survival, suggesting an important role for p27 in pancreatic tumorigenesis. Here, we sought to determine how p27 might contribute to early events leading to tumor development in the pancreas. We found that K-Ras activation in the pancreas causes p27 mislocalization at pre-neoplastic stages. Moreover, loss of p27 or expression of a mutant p27 that does not bind cyclin-CDKs causes the mislocalization of several acinar polarity markers associated with metaplasia and induces the nuclear expression of Sox9 and Pdx1 two transcription factors involved in acinar-to-ductal metaplasia. Finally, we found that p27 directly represses transcription of Sox9, but not that of Pdx1. Thus, our results suggest that K-Ras activation, the earliest known event in pancreatic carcinogenesis, may cause loss of nuclear p27 expression which results in derepression of Sox9, triggering reprogramming of acinar cells and metaplasia.Impact Journals2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/105927Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.18632/oncotarget.5770Oncotarget, 2015, vol. 6, num. 34, p. 35880-35892https://doi.org/10.18632/oncotarget.5770cc-by (c) Jeannot, Pauline et al., 2015http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1059272026-05-27T06:46:51Z
dc.title.none.fl_str_mv Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.
title Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.
spellingShingle Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.
Jeannot, Pauline
Pàncrees
Cicle cel·lular
Inhibidors enzimàtics
Proteïnes quinases
Pancreas
Cell cycle
Enzyme inhibitors
Protein kinases
title_short Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.
title_full Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.
title_fullStr Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.
title_full_unstemmed Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.
title_sort Loss of p27/Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.
dc.creator.none.fl_str_mv Jeannot, Pauline
Callot, Caroline
Baer, Romain
Duquesnes, Nicolas
Guerra, Carmen
Guillermet-Guibert, Julie
Bachs Valldeneu, Oriol
Besson, Arnaud
author Jeannot, Pauline
author_facet Jeannot, Pauline
Callot, Caroline
Baer, Romain
Duquesnes, Nicolas
Guerra, Carmen
Guillermet-Guibert, Julie
Bachs Valldeneu, Oriol
Besson, Arnaud
author_role author
author2 Callot, Caroline
Baer, Romain
Duquesnes, Nicolas
Guerra, Carmen
Guillermet-Guibert, Julie
Bachs Valldeneu, Oriol
Besson, Arnaud
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Pàncrees
Cicle cel·lular
Inhibidors enzimàtics
Proteïnes quinases
Pancreas
Cell cycle
Enzyme inhibitors
Protein kinases
topic Pàncrees
Cicle cel·lular
Inhibidors enzimàtics
Proteïnes quinases
Pancreas
Cell cycle
Enzyme inhibitors
Protein kinases
description p27Kip1 (p27) is a negative regulator of proliferation and a tumor suppressor via the inhibition of cyclin-CDK activity in the nucleus. p27 is also involved in the regulation of other cellular processes, including transcription by acting as a transcriptional co-repressor. Loss of p27 expression is frequently observed in pancreatic adenocarcinomas in human and is associated with decreased patient survival. Similarly, in a mouse model of K-Ras-driven pancreatic cancer, loss of p27 accelerates tumor development and shortens survival, suggesting an important role for p27 in pancreatic tumorigenesis. Here, we sought to determine how p27 might contribute to early events leading to tumor development in the pancreas. We found that K-Ras activation in the pancreas causes p27 mislocalization at pre-neoplastic stages. Moreover, loss of p27 or expression of a mutant p27 that does not bind cyclin-CDKs causes the mislocalization of several acinar polarity markers associated with metaplasia and induces the nuclear expression of Sox9 and Pdx1 two transcription factors involved in acinar-to-ductal metaplasia. Finally, we found that p27 directly represses transcription of Sox9, but not that of Pdx1. Thus, our results suggest that K-Ras activation, the earliest known event in pancreatic carcinogenesis, may cause loss of nuclear p27 expression which results in derepression of Sox9, triggering reprogramming of acinar cells and metaplasia.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/105927
url https://hdl.handle.net/2445/105927
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.5770
Oncotarget, 2015, vol. 6, num. 34, p. 35880-35892
https://doi.org/10.18632/oncotarget.5770
dc.rights.none.fl_str_mv cc-by (c) Jeannot, Pauline et al., 2015
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Jeannot, Pauline et al., 2015
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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