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.

mir-35 is involved in intestine cell G1/S transition and germ cell proliferation in C. elegans

“…The SCF complex functions as an E3 ubiquitin ligase and degrades candidate target proteins, including CYE-1 (cyclin E-1) [32,33] and CDC-25.1 (Cell Division Cycle related) [34], to negatively regulate G1/S transition. In C. elegans, cul-1 (CULlin) and lin-23 (abnormal cell LINeage) have been identified to encode main components of this complex [35,36], and depletion of lin-23 leads to intestinal hyperplasia [34].…”

ASPP2 inhibits APP‐BP1‐mediated NEDD8 conjugation to cullin‐1 and decreases APP‐BP1‐induced cell proliferation and neuronal apoptosis

“…They also accumulate cyclin E, and b-catenin, a mediator of the Wnt/wingless signaling pathway. The knockout animal data suggest that Cul-1 is required for the developmentally regulated G1 to G0 transition (Kipreos et al 1996;Dealy et al 1999;Wang et al 1999).…”

Oncogenic aberrations of cullin-dependent ubiquitin ligases

“…Moreover, Cul1 is necessary for proper cell cycle exit. In mice, loss of Cul1 results in early embryonic lethality (Dealy et al, 1999;Wang et al, 1999). Cul1-deficient embryos implant in the uterine wall but do not develop beyond embryonic day 5.5, before the onset of gastrulation.…”