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dc.contributor.authorSabherwal, Nitin; orcid: 0000-0002-5808-6201
dc.contributor.authorRowntree, Andrew; orcid: 0000-0003-3220-0720
dc.contributor.authorMarinopoulou, Elli; orcid: 0000-0002-6379-5168
dc.contributor.authorPettini, Tom
dc.contributor.authorHourihane, Sean; orcid: 0000-0001-8327-2578
dc.contributor.authorThomas, Riba
dc.contributor.authorSoto, Ximena
dc.contributor.authorKursawe, Jochen; orcid: 0000-0002-0314-9623
dc.contributor.authorPapalopulu, Nancy
dc.date.accessioned2021-11-16T02:35:30Z
dc.date.available2021-11-16T02:35:30Z
dc.date.issued2021-11-09
dc.date.submitted2021-07-29
dc.identifierpubmed: 34725165
dc.identifierpii: 2113527118
dc.identifierdoi: 10.1073/pnas.2113527118
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, volume 118, issue 45
dc.identifier.urihttp://hdl.handle.net/10034/626347
dc.descriptionFrom PubMed via Jisc Publications Router
dc.descriptionHistory: received 2021-07-29, accepted 2021-09-08
dc.descriptionPublication status: ppublish
dc.description.abstractHere, we study the dynamical expression of endogenously labeled Hes1, a transcriptional repressor implicated in controlling cell proliferation, to understand how cell-cycle length heterogeneity is generated in estrogen receptor (ER) breast cancer cells. We find that Hes1 shows oscillatory expression with ∼25 h periodicity and during each cell cycle has a variable peak in G1, a trough around G1-S transition, and a less variable second peak in G2/M. Compared to other subpopulations, the cell cycle in CD44 CD24 cancer stem cells is longest and most variable. Most cells divide around the peak of the Hes1 expression wave, but preceding mitoses in slow dividing CD44 CD24 cells appear phase-shifted, resulting in a late-onset Hes1 peak in G1. The position, duration, and shape of this peak, rather than the Hes1 expression levels, are good predictors of cell-cycle length. Diminishing Hes1 oscillations by enforcing sustained expression slows down the cell cycle, impairs proliferation, abolishes the dynamic expression of p21, and increases the percentage of CD44 CD24 cells. Reciprocally, blocking the cell cycle causes an elongation of Hes1 periodicity, suggesting a bidirectional interaction of the Hes1 oscillator and the cell cycle. We propose that Hes1 oscillations are functionally important for the efficient progression of the cell cycle and that the position of mitosis in relation to the Hes1 wave underlies cell-cycle length heterogeneity in cancer cell subpopulations. [Abstract copyright: Copyright © 2021 the Author(s). Published by PNAS.]
dc.languageeng
dc.sourceeissn: 1091-6490
dc.subjectcell cycle
dc.subjectcancer stem cell fate
dc.subjectoscillations
dc.subjectHes1
dc.subjectnongenetic heterogeneity
dc.titleDifferential phase register of Hes1 oscillations with mitoses underlies cell-cycle heterogeneity in ER
dc.typearticle
dc.date.updated2021-11-16T02:35:30Z
dc.date.accepted2021-09-08


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