Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin

Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulat...

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Authors: Grande, Lara, Bretones, Gabriel, Rosa-Garrido, Manuel, Garrido-Martin, Eva M., Hernandez, Teresa, Fraile, Susana, Botella, Luisa M., Alava, Enrique de, Vidal-Bel, August, García del Muro Solans, Xavier, Villanueva Garatachea, Alberto, Delgado, M. Dolores, Fernandez-Luna, Jose L.
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:2445/177420
Online Access:https://hdl.handle.net/2445/177420
Access Level:Open access
Keyword:Apoptosi
Fisiologia
Càncer
Cisplatí
ADN
Expressió gènica
Proteïnes supressores de tumors
Apoptosis
Physiology
Cancer
Cisplatin
DNA
Gene expression
Tumor suppressor protein
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oai_identifier_str oai:diposit.ub.edu:2445/177420
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repository_id_str
spelling Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatinGrande, LaraBretones, GabrielRosa-Garrido, ManuelGarrido-Martin, Eva M.Hernandez, TeresaFraile, SusanaBotella, Luisa M.Alava, Enrique deVidal-Bel, AugustGarcía del Muro Solans, XavierVillanueva Garatachea, AlbertoDelgado, M. DoloresFernandez-Luna, Jose L.ApoptosiFisiologiaCàncerCisplatíADNExpressió gènicaProteïnes supressores de tumorsApoptosisPhysiologyCancerCisplatinDNAGene expressionTumor suppressor proteinTesticular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin-sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform ΔNp73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up-regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response.American Society for Biochemistry and Molecular Biology2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/177420Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1074/jbc.M112.376319Journal of Biological Chemistry, 2012, vol. 287, num. 32, p. 26495-26505https://doi.org/10.1074/jbc.M112.376319(c) American Society for Biochemistry and Molecular Biology, 2012info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1774202026-05-27T06:46:51Z
dc.title.none.fl_str_mv Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin
title Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin
spellingShingle Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin
Grande, Lara
Apoptosi
Fisiologia
Càncer
Cisplatí
ADN
Expressió gènica
Proteïnes supressores de tumors
Apoptosis
Physiology
Cancer
Cisplatin
DNA
Gene expression
Tumor suppressor protein
title_short Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin
title_full Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin
title_fullStr Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin
title_full_unstemmed Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin
title_sort Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin
dc.creator.none.fl_str_mv Grande, Lara
Bretones, Gabriel
Rosa-Garrido, Manuel
Garrido-Martin, Eva M.
Hernandez, Teresa
Fraile, Susana
Botella, Luisa M.
Alava, Enrique de
Vidal-Bel, August
García del Muro Solans, Xavier
Villanueva Garatachea, Alberto
Delgado, M. Dolores
Fernandez-Luna, Jose L.
author Grande, Lara
author_facet Grande, Lara
Bretones, Gabriel
Rosa-Garrido, Manuel
Garrido-Martin, Eva M.
Hernandez, Teresa
Fraile, Susana
Botella, Luisa M.
Alava, Enrique de
Vidal-Bel, August
García del Muro Solans, Xavier
Villanueva Garatachea, Alberto
Delgado, M. Dolores
Fernandez-Luna, Jose L.
author_role author
author2 Bretones, Gabriel
Rosa-Garrido, Manuel
Garrido-Martin, Eva M.
Hernandez, Teresa
Fraile, Susana
Botella, Luisa M.
Alava, Enrique de
Vidal-Bel, August
García del Muro Solans, Xavier
Villanueva Garatachea, Alberto
Delgado, M. Dolores
Fernandez-Luna, Jose L.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Apoptosi
Fisiologia
Càncer
Cisplatí
ADN
Expressió gènica
Proteïnes supressores de tumors
Apoptosis
Physiology
Cancer
Cisplatin
DNA
Gene expression
Tumor suppressor protein
topic Apoptosi
Fisiologia
Càncer
Cisplatí
ADN
Expressió gènica
Proteïnes supressores de tumors
Apoptosis
Physiology
Cancer
Cisplatin
DNA
Gene expression
Tumor suppressor protein
description Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin-sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform ΔNp73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up-regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response.
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/2445/177420
url https://hdl.handle.net/2445/177420
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.M112.376319
Journal of Biological Chemistry, 2012, vol. 287, num. 32, p. 26495-26505
https://doi.org/10.1074/jbc.M112.376319
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 (Patologia i Terapèutica Experimental)
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_ 1869406388658110464
score 15,300719

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