Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E.
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.
Wang
Y
Y
Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Canada.
Penfold
S
S
Tang
X
X
Hattori
N
N
Riley
P
P
Harper
J W
JW
Cross
J C
JC
Tyers
M
M
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
D019927:Cyclin E; D012333:RNA, Messenger; D044843:SKP Cullin F-Box Protein Ligases; D010453:Peptide Synthases