Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes

Autores
Cooke, Mariana; Casado Medrano, Victoria; Ann, Jihyae; Lee, Jeewoo; Blumberg, Peter M.; Abba, Martín Carlos; Kazanietz, Marcelo Gabriel
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation ofPKC isozyme-specific modulators acting via the C1 domain, the binding site forthe lipid second messenger diacylglycerol (DAG) and the phorbol ester tumorpromoters. Synthetic efforts had recently led to the identification of AJH-836, aDAG-lactone with preferential affinity for novel isozymes (nPKCs) relative toclassical PKCs (cPKCs). Here, we compared the ability of AJH-836 and aprototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to inducechanges in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereasAJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1, MMP9,and MMP10 were among the genes most prominently induced by PMA, an effectimpaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive genesignature analysis and bioinformatics efforts, including functional enrichmentand transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differentialinvolvement of individual PKC isozymes in the control of gene expression, ourstudies emphasize the importance of generating targeted C1 domain ligands capableof differentially regulating PKC isozyme-specific function in cellular models.
Fil: Cooke, Mariana. University of Pennsylvania; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
Fil: Casado Medrano, Victoria. University of Pennsylvania; Estados Unidos
Fil: Ann, Jihyae. Seoul National University; Corea del Sur
Fil: Lee, Jeewoo. Seoul National University; Corea del Sur
Fil: Blumberg, Peter M.. No especifíca;
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados Unidos
Materia
LUNG
RACGEF
PRKC
DAG
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/118869
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/118869
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymesCooke, MarianaCasado Medrano, VictoriaAnn, JihyaeLee, JeewooBlumberg, Peter M.Abba, Martín CarlosKazanietz, Marcelo GabrielLUNGRACGEFPRKCDAGhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation ofPKC isozyme-specific modulators acting via the C1 domain, the binding site forthe lipid second messenger diacylglycerol (DAG) and the phorbol ester tumorpromoters. Synthetic efforts had recently led to the identification of AJH-836, aDAG-lactone with preferential affinity for novel isozymes (nPKCs) relative toclassical PKCs (cPKCs). Here, we compared the ability of AJH-836 and aprototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to inducechanges in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereasAJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1, MMP9,and MMP10 were among the genes most prominently induced by PMA, an effectimpaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive genesignature analysis and bioinformatics efforts, including functional enrichmentand transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differentialinvolvement of individual PKC isozymes in the control of gene expression, ourstudies emphasize the importance of generating targeted C1 domain ligands capableof differentially regulating PKC isozyme-specific function in cellular models.Fil: Cooke, Mariana. University of Pennsylvania; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Casado Medrano, Victoria. University of Pennsylvania; Estados UnidosFil: Ann, Jihyae. Seoul National University; Corea del SurFil: Lee, Jeewoo. Seoul National University; Corea del SurFil: Blumberg, Peter M.. No especifíca;Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados UnidosNature2019-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/118869Cooke, Mariana; Casado Medrano, Victoria; Ann, Jihyae; Lee, Jeewoo; Blumberg, Peter M.; et al.; Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes; Nature; Scientific Report; 9; 4-2019; 1-152045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-019-42581-4info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-019-42581-4info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:20:29Zoai:ri.conicet.gov.ar:11336/118869instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:20:29.727CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
title Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
spellingShingle Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
Cooke, Mariana
LUNG
RACGEF
PRKC
DAG
title_short Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
title_full Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
title_fullStr Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
title_full_unstemmed Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
title_sort Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
dc.creator.none.fl_str_mv Cooke, Mariana
Casado Medrano, Victoria
Ann, Jihyae
Lee, Jeewoo
Blumberg, Peter M.
Abba, Martín Carlos
Kazanietz, Marcelo Gabriel
author Cooke, Mariana
author_facet Cooke, Mariana
Casado Medrano, Victoria
Ann, Jihyae
Lee, Jeewoo
Blumberg, Peter M.
Abba, Martín Carlos
Kazanietz, Marcelo Gabriel
author_role author
author2 Casado Medrano, Victoria
Ann, Jihyae
Lee, Jeewoo
Blumberg, Peter M.
Abba, Martín Carlos
Kazanietz, Marcelo Gabriel
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv LUNG
RACGEF
PRKC
DAG
topic LUNG
RACGEF
PRKC
DAG
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation ofPKC isozyme-specific modulators acting via the C1 domain, the binding site forthe lipid second messenger diacylglycerol (DAG) and the phorbol ester tumorpromoters. Synthetic efforts had recently led to the identification of AJH-836, aDAG-lactone with preferential affinity for novel isozymes (nPKCs) relative toclassical PKCs (cPKCs). Here, we compared the ability of AJH-836 and aprototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to inducechanges in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereasAJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1, MMP9,and MMP10 were among the genes most prominently induced by PMA, an effectimpaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive genesignature analysis and bioinformatics efforts, including functional enrichmentand transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differentialinvolvement of individual PKC isozymes in the control of gene expression, ourstudies emphasize the importance of generating targeted C1 domain ligands capableof differentially regulating PKC isozyme-specific function in cellular models.
Fil: Cooke, Mariana. University of Pennsylvania; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
Fil: Casado Medrano, Victoria. University of Pennsylvania; Estados Unidos
Fil: Ann, Jihyae. Seoul National University; Corea del Sur
Fil: Lee, Jeewoo. Seoul National University; Corea del Sur
Fil: Blumberg, Peter M.. No especifíca;
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados Unidos
description Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation ofPKC isozyme-specific modulators acting via the C1 domain, the binding site forthe lipid second messenger diacylglycerol (DAG) and the phorbol ester tumorpromoters. Synthetic efforts had recently led to the identification of AJH-836, aDAG-lactone with preferential affinity for novel isozymes (nPKCs) relative toclassical PKCs (cPKCs). Here, we compared the ability of AJH-836 and aprototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to inducechanges in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereasAJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1, MMP9,and MMP10 were among the genes most prominently induced by PMA, an effectimpaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive genesignature analysis and bioinformatics efforts, including functional enrichmentand transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differentialinvolvement of individual PKC isozymes in the control of gene expression, ourstudies emphasize the importance of generating targeted C1 domain ligands capableof differentially regulating PKC isozyme-specific function in cellular models.
publishDate 2019
dc.date.none.fl_str_mv 2019-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/118869
Cooke, Mariana; Casado Medrano, Victoria; Ann, Jihyae; Lee, Jeewoo; Blumberg, Peter M.; et al.; Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes; Nature; Scientific Report; 9; 4-2019; 1-15
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/118869
identifier_str_mv Cooke, Mariana; Casado Medrano, Victoria; Ann, Jihyae; Lee, Jeewoo; Blumberg, Peter M.; et al.; Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes; Nature; Scientific Report; 9; 4-2019; 1-15
2045-2322
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-019-42581-4
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-019-42581-4
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature
publisher.none.fl_str_mv Nature
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.48226

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