Fbxw8 is essential for Cul1-Cul7 complex formation and for placental development.
Cullin-based ubiquitin ligases (E3s) constitute one of the largest E3 families. Fbxw8 (also known as Fbw6 or Fbx29) is an F-box protein that is assembled with Cul7 in an SCF-like E3 complex. Here we show that Cul7 forms a heterodimeric complex with Cul1 in a manner dependent on Fbxw8. We generated mice deficient in Fbxw8 and found that Cul7 did not associate with Cul1 in cells of these mice. Two-thirds of Fbxw8-/- embryos die in utero, whereas the remaining one-third are born alive and grow to adulthood. Fbxw8-/- embryos show intrauterine growth retardation and abnormal development of the placenta, characterized by both a reduced thickness of the spongiotrophoblast layer and abnormal vessel structure in the labyrinth layer. Although the placental phenotype of Fbxw8-/- mice resembles that of Cul7-/- mice, other abnormalities of Cul7-/- mice are not apparent in Fbxw8-/- mice. These results suggest that the Cul7-based SCF-like E3 complex has both Fbxw8-dependent and Fbxw8-independent functions.
Tsunematsu
Ryosuke
R
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nishiyama
Masaaki
M
Kotoshiba
Shuhei
S
Saiga
Toru
T
Kamura
Takumi
T
Nakayama
Keiichi I
KI
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003433:Crosses, Genetic; D044842:Cullin Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000166:cytology / Q000196:embryology / Q000473:pathology; D005091:Exons / Q000235:genetics; D044783:F-Box Proteins / Q000378:metabolism*; D005260:Female; D005317:Fetal Growth Retardation; D018390:Gene Targeting; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D010641:Phenotype; D010920:Placenta / Q000002:abnormalities / Q000166:cytology / Q000196:embryology* / Q000473:pathology; D011247:Pregnancy; D011485:Protein Binding
D018797:Cell Cycle Proteins; C494817:Cul7 protein, mouse; C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; C513332:Fbxw8 protein, mouse