Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes

Transforming growth factor-β (TGF-β) plays a dual role in hepatocytes, mediating both tumor suppressor and promoter effects. The suppressor effects of the cytokine can be negatively regulated by activation of survival signals, mostly dependent on tyrosine kinase activity. The aim of our work was to...

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Authors: Ortiz, Conrad, Caja Puigsubirà, Laia, Bertran Rodríguez, Esther, González Rodríguez, Águeda, Valverde, Ángela M., Fabregat Romero, Isabel, Sancho, Patrícia
Format: article
Status:Published version
Publication Date:2012
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/181299
Online Access:https://hdl.handle.net/2445/181299
Access Level:Open access
Keyword:Proteïna-tirosina-fosfatasa
Factors de creixement
Proteïnes supressores de tumors
Protein-tyrosine phosphatase
Growth factors
Tumor suppressor protein
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spelling Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytesOrtiz, ConradCaja Puigsubirà, LaiaBertran Rodríguez, EstherGonzález Rodríguez, ÁguedaValverde, Ángela M.Fabregat Romero, IsabelSancho, PatríciaProteïna-tirosina-fosfatasaFactors de creixementProteïnes supressores de tumorsProtein-tyrosine phosphataseGrowth factorsTumor suppressor proteinTransforming growth factor-β (TGF-β) plays a dual role in hepatocytes, mediating both tumor suppressor and promoter effects. The suppressor effects of the cytokine can be negatively regulated by activation of survival signals, mostly dependent on tyrosine kinase activity. The aim of our work was to study the role of the protein-tyrosine phosphatase 1B (PTP1B) on the cellular responses to TGF-β, using for this purpose immortalized neonatal hepatocytes isolated from both PTP1B(+/+) and PTP1B(-/-) mice. We have found that PTP1B deficiency conferred resistance to TGF-β suppressor effects, such as apoptosis and growth inhibition, correlating with lower Smad2/Smad3 activation. Both responses were recovered in the presence of the general tyrosine kinase inhibitor genistein. PTP1B(-/-) cells showed elevated NF-κB activation in response to TGF-β. Knockdown of the NF-κB p65 subunit increased cell response in terms of Smads phosphorylation and apoptosis. Interestingly, these effects were accompanied by inhibition of Smad7 up-regulation. In addition, lack of PTP1B promoted an altered NADPH oxidase (NOX) expression pattern in response to TGF-β, strongly increasing the NOX1/NOX4 ratio, which was reverted by genistein and p65 knockdown. Importantly, NOX1 knockdown inhibited nuclear translocation of p65, promoted Smad phosphorylation, and decreased Smad7 levels. In summary, our results suggest that PTP1B deficiency confers resistance to TGF-β through Smad inhibition, an effect that is mediated by NOX1-dependent NF-κB activation, which in turn, increases the level of the Smad inhibitor Smad7 and participates in a positive feedback loop on NOX1 up-regulation.American Society for Biochemistry and Molecular Biology2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/181299Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1074/jbc.M111.303958Journal of Biological Chemistry, 2012, vol. 287, num. 19, p. 15263-15274https://doi.org/10.1074/jbc.M111.303958(c) American Society for Biochemistry and Molecular Biology, 2012info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1812992026-05-27T06:46:51Z
dc.title.none.fl_str_mv Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes
title Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes
spellingShingle Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes
Ortiz, Conrad
Proteïna-tirosina-fosfatasa
Factors de creixement
Proteïnes supressores de tumors
Protein-tyrosine phosphatase
Growth factors
Tumor suppressor protein
title_short Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes
title_full Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes
title_fullStr Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes
title_full_unstemmed Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes
title_sort Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes
dc.creator.none.fl_str_mv Ortiz, Conrad
Caja Puigsubirà, Laia
Bertran Rodríguez, Esther
González Rodríguez, Águeda
Valverde, Ángela M.
Fabregat Romero, Isabel
Sancho, Patrícia
author Ortiz, Conrad
author_facet Ortiz, Conrad
Caja Puigsubirà, Laia
Bertran Rodríguez, Esther
González Rodríguez, Águeda
Valverde, Ángela M.
Fabregat Romero, Isabel
Sancho, Patrícia
author_role author
author2 Caja Puigsubirà, Laia
Bertran Rodríguez, Esther
González Rodríguez, Águeda
Valverde, Ángela M.
Fabregat Romero, Isabel
Sancho, Patrícia
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïna-tirosina-fosfatasa
Factors de creixement
Proteïnes supressores de tumors
Protein-tyrosine phosphatase
Growth factors
Tumor suppressor protein
topic Proteïna-tirosina-fosfatasa
Factors de creixement
Proteïnes supressores de tumors
Protein-tyrosine phosphatase
Growth factors
Tumor suppressor protein
description Transforming growth factor-β (TGF-β) plays a dual role in hepatocytes, mediating both tumor suppressor and promoter effects. The suppressor effects of the cytokine can be negatively regulated by activation of survival signals, mostly dependent on tyrosine kinase activity. The aim of our work was to study the role of the protein-tyrosine phosphatase 1B (PTP1B) on the cellular responses to TGF-β, using for this purpose immortalized neonatal hepatocytes isolated from both PTP1B(+/+) and PTP1B(-/-) mice. We have found that PTP1B deficiency conferred resistance to TGF-β suppressor effects, such as apoptosis and growth inhibition, correlating with lower Smad2/Smad3 activation. Both responses were recovered in the presence of the general tyrosine kinase inhibitor genistein. PTP1B(-/-) cells showed elevated NF-κB activation in response to TGF-β. Knockdown of the NF-κB p65 subunit increased cell response in terms of Smads phosphorylation and apoptosis. Interestingly, these effects were accompanied by inhibition of Smad7 up-regulation. In addition, lack of PTP1B promoted an altered NADPH oxidase (NOX) expression pattern in response to TGF-β, strongly increasing the NOX1/NOX4 ratio, which was reverted by genistein and p65 knockdown. Importantly, NOX1 knockdown inhibited nuclear translocation of p65, promoted Smad phosphorylation, and decreased Smad7 levels. In summary, our results suggest that PTP1B deficiency confers resistance to TGF-β through Smad inhibition, an effect that is mediated by NOX1-dependent NF-κB activation, which in turn, increases the level of the Smad inhibitor Smad7 and participates in a positive feedback loop on NOX1 up-regulation.
publishDate 2012
dc.date.none.fl_str_mv 2012
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/2445/181299
url https://hdl.handle.net/2445/181299
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/10.1074/jbc.M111.303958
Journal of Biological Chemistry, 2012, vol. 287, num. 19, p. 15263-15274
https://doi.org/10.1074/jbc.M111.303958
dc.rights.none.fl_str_mv (c) American Society for Biochemistry and Molecular Biology, 2012
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Society for Biochemistry and Molecular Biology, 2012
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
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
_version_ 1869403272739028992
score 15,198674

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