title: Distinct activities of the anaphase-promoting complex/cyclosome (APC/C) in mouse embryonic cells.
abstract: The first differentiation event in mammalian development gives rise to the blastocyst, consisting of two cell lineages that have also segregated in how the cell cycle is structured. Pluripotent cells of the inner cell mass divide mitotically to retain a diploid DNA content, but the outer trophoblast cells can amplify their genomes more than 500-fold by undergoing multiple rounds of DNA replication, completely bypassing mitosis. Central to this striking divergence in cell cycle control is the E3 ubiquitin-ligase activity of the anaphase-promoting complex or cyclosome (APC/C). Extended suppression of APC/C activity during interphase of mouse pluripotent cells promotes rapid cell cycle progression by allowing stabilization of cyclins, whereas unopposed APC/C activity during S phase of mouse trophoblast cells triggers proteasomal-mediated degradation of geminin and giant cell formation. While differential APC/C activity might govern the atypical cell cycles observed in pre-implantation mouse embryos, geminin is a critical APC/C substrate that: (1) escapes degradation in pluripotent cells to maintain expression of Oct4, Sox2 and Nanog; and (2) mediates specification and endoreduplication when targeted for ectopic destruction in trophoblast. Thus, in contrast to trophoblast giant cells that lack geminin, geminin is preserved in both mouse pluripotent cells and non-endoreduplicating human cytotrophoblast cells.
authors.affiliation: MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Yang
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Carter
authors.forename: Yifan
authors.initials: Y
authors.lastname: Ng
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hyland
authors.forename: Kikuë
authors.initials: K
authors.lastname: Tachibana-Konwalski
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Fisher
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.forename: Roger A
authors.initials: RA
authors.lastname: Pedersen
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 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D056751:Cyclin A2 / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D062951:Endoreduplication; D064248:Geminin; D006801:Humans; D007399:Interphase; D051379:Mice; D008938:Mitosis; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D056751:Cyclin A2; D056744:Cyclin B1; C498959:Emi1 protein, mouse; D064248:Geminin; C577997:Gmnn protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases