title: Geminin escapes degradation in G1 of mouse pluripotent cells and mediates the expression of Oct4, Sox2, and Nanog.
abstract: Geminin is an essential cell-cycle protein that is only present from S phase to early mitosis in metazoan somatic cells. Genetic ablation of geminin in the mouse results in preimplantation embryonic lethality because pluripotent cells fail to form and all cells differentiate to trophoblast. Here we show that geminin is present in G1 phase of mouse pluripotent cells in contrast to somatic cells, where anaphase-promoting complex/cyclosome (APC/C)-mediated proteasomal destruction removes geminin in G1. Silencing geminin directly or by depleting the APC/C inhibitor Emi1 causes loss of stem cell identity and trophoblast differentiation of mouse embryonal carcinoma and embryonic stem cells. Depletion of cyclins A2 or B1 does not induce this effect, even though both of these APC/C substrates are also present during G1 of pluripotent cells. Crucially, geminin antagonizes the chromatin-remodeling protein Brg1 to maintain expression of Oct4, Sox2, and Nanog. Our results define a pluripotency pathway by which suppressed APC/C activity protects geminin from degradation in G1, allowing sustained expression of core pluripotency factors. Collectively, these findings link the cell cycle to the pluripotent state but also raise an unexplained paradox: How is cell-cycle progression possible in pluripotent cells when oscillations of key regulatory proteins are lost?
authors.affiliation: MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Yang
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Carter
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hyland
authors.forename: Kikuë
authors.initials: K
authors.lastname: Tachibana-Konwalski
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Laskey
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D056751:Cyclin A2 / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D054278:Embryonal Carcinoma Stem Cells / Q000166:cytology; D053595:Embryonic Stem Cells / Q000166:cytology; D016193:G1 Phase; D064248:Geminin; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D056751:Cyclin A2; D056744:Cyclin B1; D064248:Geminin; C577997:Gmnn protein, mouse; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C513194:Smarca4 protein, mouse; D004265:DNA Helicases