Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation

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dc.contributor.authorWhite, J.
dc.contributor.authorStead, E.
dc.contributor.authorFaast, R.
dc.contributor.authorConn, S.
dc.contributor.authorCartwright, P.
dc.contributor.authorDalton, S.
dc.date.issued2005
dc.description.abstractTo understand cell cycle control mechanisms in early development and how they change during differentiation, we used embryonic stem cells to model embryonic events. Our results demonstrate that as pluripotent cells differentiate, the length of G₁ phase increases substantially. At the molecular level, this is associated with a significant change in the size of active cyclin-dependent kinase (Cdk) complexes, the establishment of cell cycle-regulated Cdk2 activity and the activation of a functional Rb–E2F pathway. The switch from constitutive to cell cycle-dependent Cdk2 activity coincides with temporal changes in cyclin A2 and E1 protein levels during the cell cycle. Transcriptional mechanisms underpin the down-regulation of cyclin levels and the establishment of their periodicity during differentiation. As pluripotent cells differentiate and pRb/p107 kinase activities become cell cycle dependent, the E2F–pRb pathway is activated and imposes cell cycle-regulated transcriptional control on E2F target genes, such as cyclin E1. These results suggest the existence of a feedback loop where Cdk2 controls its own activity through regulation of cyclin E1 transcription. Changes in rates of cell division, cell cycle structure and the establishment of cell cycle-regulated Cdk2 activity can therefore be explained by activation of the E2F–pRb pathway.
dc.description.statementofresponsibilityJosephine White, Elaine Stead, Renate Faast, Simon Conn, Peter Cartwright, and Stephen Dalton
dc.identifier.citationMolecular Biology of the Cell, 2005; 16(4):2018-2027
dc.identifier.doi10.1091/mbc.E04-12-1056
dc.identifier.issn1059-1524
dc.identifier.issn1939-4586
dc.identifier.urihttp://hdl.handle.net/2440/27486
dc.language.isoen
dc.publisherAmer Soc Cell Biology
dc.source.urihttps://doi.org/10.1091/mbc.e04-12-1056
dc.subjectCells, Cultured
dc.subjectStem Cells
dc.subjectAnimals
dc.subjectMice
dc.subjectCyclin-Dependent Kinases
dc.subjectCyclin E
dc.subjectCell Cycle Proteins
dc.subjectDNA-Binding Proteins
dc.subjectRetinoblastoma Protein
dc.subjectTranscription Factors
dc.subjectRNA, Messenger
dc.subjectCell Cycle
dc.subjectCell Differentiation
dc.subjectTranscription, Genetic
dc.subjectDown-Regulation
dc.subjectE2F Transcription Factors
dc.subjectEmbryo, Mammalian
dc.subjectPromoter Regions, Genetic
dc.titleDevelopmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation
dc.typeJournal article
pubs.publication-statusPublished

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