title: G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells.
abstract: Progression of mammalian cells through the G1 and S phases of the cell cycle is driven by the D-type and E-type cyclins. According to the current models, at least one of these cyclin families must be present to allow cell proliferation. Here, we show that several cell types can proliferate in the absence of all G1 cyclins. However, following ablation of G1 cyclins, embryonic stem (ES) cells attenuated their pluripotent characteristics, with the majority of cells acquiring the trophectodermal cell fate. We established that G1 cyclins, together with their associated cyclin-dependent kinases (CDKs), phosphorylate and stabilize the core pluripotency factors Nanog, Sox2 and Oct4. Treatment of murine ES cells, patient-derived glioblastoma tumour-initiating cells, or triple-negative breast cancer cells with a CDK inhibitor strongly decreased Sox2 and Oct4 levels. Our findings suggest that CDK inhibition might represent an attractive therapeutic strategy by targeting glioblastoma tumour-initiating cells, which depend on Sox2 to maintain their tumorigenic potential.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michowski
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Naoe Taira
authors.initials: NT
authors.lastname: Nihira
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Chick
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Geng
authors.affiliation: Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Alice Y
authors.initials: AY
authors.lastname: Meng
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Alban
authors.identifier: 0000-0002-4924-8520
authors.initials: A
authors.lastname: Ordureau
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kołodziejczyk
authors.affiliation: Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, Massachusetts 01536, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation; D056766:Cyclin G1 / Q000378:metabolism*; D004247:DNA / Q000032:analysis; D004622:Embryo, Mammalian / Q000166:cytology; D044127:Epigenesis, Genetic; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D021621:Imaging, Three-Dimensional; D008239:Lysine / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D012313:RNA / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology; D059470:Tetraspanins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D056766:Cyclin G1; D006657:Histones; D006728:Hormones; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D013256:Steroids; D059470:Tetraspanins; D012313:RNA; D004247:DNA; D008239:Lysine