E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation

Autores
Carcagno, A.L.; Marazita, M.C.; Ogara, M.F.; Ceruti, J.M.; Sonzogni, S.V.; Scassa, M.E.; Giono, L.E.; Cánepa, E.T.
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: A central aspect of development and disease is the control of cell proliferation through regulation of the mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under normal conditions, a feature reminiscent of cyclins. Methodology/Principal Findings: In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19 periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased the fraction of cells in S phase. Conclusions/Significance: The results described here support a model of normal cell cycle progression in which, following phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes, bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional mechanism to limit E2F activity. © 2011 Carcagno et al.
Fil:Carcagno, A.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Marazita, M.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Ogara, M.F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Ceruti, J.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Sonzogni, S.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Scassa, M.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Giono, L.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Cánepa, E.T. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fuente
PLoS ONE 2011;6(7)
Materia
cyclin dependent kinase inhibitor 2D
cyclin E
transcription factor E2F1
CCNE1 protein, human
CDKN2D protein, human
cyclin dependent kinase inhibitor 2D
cyclin E
oncoprotein
transcription factor E2F1
animal cell
article
cell cycle progression
cell cycle S phase
cell proliferation
controlled study
embryo
human
human cell
nonhuman
promoter region
protein expression
transcription regulation
upregulation
animal
binding site
biological model
cell cycle
cell line
cell proliferation
feedback system
genetic transcription
genetics
metabolism
molecular genetics
nucleotide sequence
periodicity
protein binding
upregulation
Animals
Base Sequence
Binding Sites
Cell Cycle
Cell Line
Cell Proliferation
Conserved Sequence
Cyclin E
Cyclin-Dependent Kinase Inhibitor p19
E2F1 Transcription Factor
Feedback, Physiological
Humans
Models, Biological
Molecular Sequence Data
Oncogene Proteins
Periodicity
Promoter Regions, Genetic
Protein Binding
Transcription, Genetic
Up-Regulation
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by/2.5/ar
Repositorio
Biblioteca Digital (UBA-FCEN)
Institución
Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
OAI Identificador
paperaa:paper_19326203_v6_n7_p_Carcagno

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oai_identifier_str paperaa:paper_19326203_v6_n7_p_Carcagno
network_acronym_str BDUBAFCEN
repository_id_str 1896
network_name_str Biblioteca Digital (UBA-FCEN)
spelling E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferationCarcagno, A.L.Marazita, M.C.Ogara, M.F.Ceruti, J.M.Sonzogni, S.V.Scassa, M.E.Giono, L.E.Cánepa, E.T.cyclin dependent kinase inhibitor 2Dcyclin Etranscription factor E2F1CCNE1 protein, humanCDKN2D protein, humancyclin dependent kinase inhibitor 2Dcyclin Eoncoproteintranscription factor E2F1animal cellarticlecell cycle progressioncell cycle S phasecell proliferationcontrolled studyembryohumanhuman cellnonhumanpromoter regionprotein expressiontranscription regulationupregulationanimalbinding sitebiological modelcell cyclecell linecell proliferationfeedback systemgenetic transcriptiongeneticsmetabolismmolecular geneticsnucleotide sequenceperiodicityprotein bindingupregulationAnimalsBase SequenceBinding SitesCell CycleCell LineCell ProliferationConserved SequenceCyclin ECyclin-Dependent Kinase Inhibitor p19E2F1 Transcription FactorFeedback, PhysiologicalHumansModels, BiologicalMolecular Sequence DataOncogene ProteinsPeriodicityPromoter Regions, GeneticProtein BindingTranscription, GeneticUp-RegulationBackground: A central aspect of development and disease is the control of cell proliferation through regulation of the mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under normal conditions, a feature reminiscent of cyclins. Methodology/Principal Findings: In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19 periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased the fraction of cells in S phase. Conclusions/Significance: The results described here support a model of normal cell cycle progression in which, following phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes, bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional mechanism to limit E2F activity. © 2011 Carcagno et al.Fil:Carcagno, A.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Marazita, M.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Ogara, M.F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Ceruti, J.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Sonzogni, S.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Scassa, M.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Giono, L.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Cánepa, E.T. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.2011info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://hdl.handle.net/20.500.12110/paper_19326203_v6_n7_p_CarcagnoPLoS ONE 2011;6(7)reponame:Biblioteca Digital (UBA-FCEN)instname:Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturalesinstacron:UBA-FCENenginfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/2.5/ar2025-09-29T13:43:05Zpaperaa:paper_19326203_v6_n7_p_CarcagnoInstitucionalhttps://digital.bl.fcen.uba.ar/Universidad públicaNo correspondehttps://digital.bl.fcen.uba.ar/cgi-bin/oaiserver.cgiana@bl.fcen.uba.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:18962025-09-29 13:43:07.091Biblioteca Digital (UBA-FCEN) - Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturalesfalse
dc.title.none.fl_str_mv E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation
title E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation
spellingShingle E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation
Carcagno, A.L.
cyclin dependent kinase inhibitor 2D
cyclin E
transcription factor E2F1
CCNE1 protein, human
CDKN2D protein, human
cyclin dependent kinase inhibitor 2D
cyclin E
oncoprotein
transcription factor E2F1
animal cell
article
cell cycle progression
cell cycle S phase
cell proliferation
controlled study
embryo
human
human cell
nonhuman
promoter region
protein expression
transcription regulation
upregulation
animal
binding site
biological model
cell cycle
cell line
cell proliferation
feedback system
genetic transcription
genetics
metabolism
molecular genetics
nucleotide sequence
periodicity
protein binding
upregulation
Animals
Base Sequence
Binding Sites
Cell Cycle
Cell Line
Cell Proliferation
Conserved Sequence
Cyclin E
Cyclin-Dependent Kinase Inhibitor p19
E2F1 Transcription Factor
Feedback, Physiological
Humans
Models, Biological
Molecular Sequence Data
Oncogene Proteins
Periodicity
Promoter Regions, Genetic
Protein Binding
Transcription, Genetic
Up-Regulation
title_short E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation
title_full E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation
title_fullStr E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation
title_full_unstemmed E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation
title_sort E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation
dc.creator.none.fl_str_mv Carcagno, A.L.
Marazita, M.C.
Ogara, M.F.
Ceruti, J.M.
Sonzogni, S.V.
Scassa, M.E.
Giono, L.E.
Cánepa, E.T.
author Carcagno, A.L.
author_facet Carcagno, A.L.
Marazita, M.C.
Ogara, M.F.
Ceruti, J.M.
Sonzogni, S.V.
Scassa, M.E.
Giono, L.E.
Cánepa, E.T.
author_role author
author2 Marazita, M.C.
Ogara, M.F.
Ceruti, J.M.
Sonzogni, S.V.
Scassa, M.E.
Giono, L.E.
Cánepa, E.T.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cyclin dependent kinase inhibitor 2D
cyclin E
transcription factor E2F1
CCNE1 protein, human
CDKN2D protein, human
cyclin dependent kinase inhibitor 2D
cyclin E
oncoprotein
transcription factor E2F1
animal cell
article
cell cycle progression
cell cycle S phase
cell proliferation
controlled study
embryo
human
human cell
nonhuman
promoter region
protein expression
transcription regulation
upregulation
animal
binding site
biological model
cell cycle
cell line
cell proliferation
feedback system
genetic transcription
genetics
metabolism
molecular genetics
nucleotide sequence
periodicity
protein binding
upregulation
Animals
Base Sequence
Binding Sites
Cell Cycle
Cell Line
Cell Proliferation
Conserved Sequence
Cyclin E
Cyclin-Dependent Kinase Inhibitor p19
E2F1 Transcription Factor
Feedback, Physiological
Humans
Models, Biological
Molecular Sequence Data
Oncogene Proteins
Periodicity
Promoter Regions, Genetic
Protein Binding
Transcription, Genetic
Up-Regulation
topic cyclin dependent kinase inhibitor 2D
cyclin E
transcription factor E2F1
CCNE1 protein, human
CDKN2D protein, human
cyclin dependent kinase inhibitor 2D
cyclin E
oncoprotein
transcription factor E2F1
animal cell
article
cell cycle progression
cell cycle S phase
cell proliferation
controlled study
embryo
human
human cell
nonhuman
promoter region
protein expression
transcription regulation
upregulation
animal
binding site
biological model
cell cycle
cell line
cell proliferation
feedback system
genetic transcription
genetics
metabolism
molecular genetics
nucleotide sequence
periodicity
protein binding
upregulation
Animals
Base Sequence
Binding Sites
Cell Cycle
Cell Line
Cell Proliferation
Conserved Sequence
Cyclin E
Cyclin-Dependent Kinase Inhibitor p19
E2F1 Transcription Factor
Feedback, Physiological
Humans
Models, Biological
Molecular Sequence Data
Oncogene Proteins
Periodicity
Promoter Regions, Genetic
Protein Binding
Transcription, Genetic
Up-Regulation
dc.description.none.fl_txt_mv Background: A central aspect of development and disease is the control of cell proliferation through regulation of the mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under normal conditions, a feature reminiscent of cyclins. Methodology/Principal Findings: In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19 periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased the fraction of cells in S phase. Conclusions/Significance: The results described here support a model of normal cell cycle progression in which, following phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes, bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional mechanism to limit E2F activity. © 2011 Carcagno et al.
Fil:Carcagno, A.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Marazita, M.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Ogara, M.F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Ceruti, J.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Sonzogni, S.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Scassa, M.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Giono, L.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Cánepa, E.T. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
description Background: A central aspect of development and disease is the control of cell proliferation through regulation of the mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under normal conditions, a feature reminiscent of cyclins. Methodology/Principal Findings: In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19 periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased the fraction of cells in S phase. Conclusions/Significance: The results described here support a model of normal cell cycle progression in which, following phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes, bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional mechanism to limit E2F activity. © 2011 Carcagno et al.
publishDate 2011
dc.date.none.fl_str_mv 2011
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/20.500.12110/paper_19326203_v6_n7_p_Carcagno
url http://hdl.handle.net/20.500.12110/paper_19326203_v6_n7_p_Carcagno
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/2.5/ar
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/2.5/ar
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv PLoS ONE 2011;6(7)
reponame:Biblioteca Digital (UBA-FCEN)
instname:Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
instacron:UBA-FCEN
reponame_str Biblioteca Digital (UBA-FCEN)
collection Biblioteca Digital (UBA-FCEN)
instname_str Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
instacron_str UBA-FCEN
institution UBA-FCEN
repository.name.fl_str_mv Biblioteca Digital (UBA-FCEN) - Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
repository.mail.fl_str_mv ana@bl.fcen.uba.ar
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