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dc.contributor.author
Cooke, Mariana
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dc.contributor.author
Casado Medrano, Victoria
dc.contributor.author
Ann, Jihyae
dc.contributor.author
Lee, Jeewoo
dc.contributor.author
Blumberg, Peter M.
dc.contributor.author
Abba, Martín Carlos
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dc.contributor.author
Kazanietz, Marcelo Gabriel
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dc.date.available
2020-11-24T15:35:44Z
dc.date.issued
2019-04
dc.identifier.citation
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
dc.identifier.issn
2045-2322
dc.identifier.uri
http://hdl.handle.net/11336/118869
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Nature
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
LUNG
dc.subject
RACGEF
dc.subject
PRKC
dc.subject
DAG
dc.subject.classification
Bioquímica y Biología Molecular
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Differential regulation of gene expression by diacyglycerol-lactones and phorbol esters via selective activation of protein kinase c isozymes
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2020-11-19T15:51:29Z
dc.journal.number
9
dc.journal.pagination
1-15
dc.journal.pais
Reino Unido
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dc.journal.ciudad
London
dc.description.fil
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
dc.description.fil
Fil: Casado Medrano, Victoria. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Ann, Jihyae. Seoul National University; Corea del Sur
dc.description.fil
Fil: Lee, Jeewoo. Seoul National University; Corea del Sur
dc.description.fil
Fil: Blumberg, Peter M.. No especifíca;
dc.description.fil
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
dc.description.fil
Fil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados Unidos
dc.journal.title
Scientific Report
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1038/s41598-019-42581-4
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-019-42581-4
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