title: Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E.
abstract: The stability of many proteins is controlled by the ubiquitin proteolytic system, which recognizes specific substrates through the action of E3 ubiquitin ligases [1]. The SCFs are a recently described class of ubiquitin ligase that target a number of cell cycle regulators and other proteins for degradation in both yeast and mammalian cells [2] [3] [4] [5] [6]. Each SCF complex is composed of the core protein subunits Skp1, Rbx1 and Cul1 (known as Cdc53 in yeast), and substrate-specific adaptor subunits called F-box proteins [2] [3] [4]. To understand the physiological role of SCF complexes in mammalian cells, we generated mice carrying a deletion in the Cul1 gene. Cul1(-/-) embryos arrested around embryonic day 6.5 (E6.5) before the onset of gastrulation. In all cells of the mutant embryos, cyclin E protein, but not mRNA, was highly elevated. Outgrowths of Cul1(-/-) blastocysts had limited proliferative capacity in vitro and accumulated cyclin E in all cells. Within Cul1(-/-) blastocyst cultures, trophoblast giant cells continued to endocycle despite the elevated cyclin E levels. These results suggest that cyclin E abundance is controlled by SCF activity, possibly through SCF-dependent degradation of cyclin E.
authors.affiliation: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Penfold
authors.forename: X
authors.initials: X
authors.lastname: Tang
authors.forename: N
authors.initials: N
authors.lastname: Hattori
authors.forename: P
authors.initials: P
authors.lastname: Riley
authors.forename: J W
authors.initials: JW
authors.lastname: Harper
authors.forename: J C
authors.initials: JC
authors.lastname: Cross
authors.forename: M
authors.initials: M
authors.lastname: Tyers
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D005314:Embryonic and Fetal Development / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005865:Gestational Age; D051379:Mice; D018345:Mice, Knockout; D010453:Peptide Synthases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D011247:Pregnancy; D020836:Protein Structure, Quaternary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases
chemical_list: D019927:Cyclin E; D012333:RNA, Messenger; D044843:SKP Cullin F-Box Protein Ligases; D010453:Peptide Synthases