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
- 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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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 |
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Biblioteca Digital (UBA-FCEN) |
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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 |
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ana@bl.fcen.uba.ar |
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