Skp2 promotes adipocyte differentiation via a p27Kip1-independent mechanism in primary mouse embryonic fibroblasts.
Skp2, the substrate-binding subunit of an SCF ubiquitin ligase complex, is a key regulator of cell cycle progression that targets substrates for degradation by the 26S proteasome. We have now shown that ablation of Skp2 in primary mouse embryonic fibroblasts (MEFs) results both in impairment of adipocyte differentiation and in the accumulation of the cyclin-dependent kinase inhibitor p27(Kip1), a principal target of the SCF(Skp2) complex. Genetic ablation of p27(Kip1) in MEFs promoted both lipid accumulation and adipocyte-specific gene expression. However, depletion of p27(Kip1) by adenovirus-mediated RNA interference failed to correct the impairment of adipocyte differentiation in Skp2(-/-) MEFs. In contrast, troglitazone, a high-affinity ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), largely restored lipid accumulation and PPARgamma gene expression in Skp2(-/-) MEFs. Our data suggest that Skp2 plays an essential role in adipogenesis in MEFs in a manner that is at least in part independent of regulation of p27(Kip1) expression.
Okada
Mitsuru
M
Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Sakai
Tamon
T
Nakamura
Takehiro
T
Tamamori-Adachi
Mimi
M
Kitajima
Shigetaka
S
Matsuki
Yasushi
Y
Watanabe
Eijiro
E
Hiramatsu
Ryuji
R
Sakaue
Hiroshi
H
Kasuga
Masato
M
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
C493961:Cdkn1b protein, mouse; D002839:Chromans; D044786:S-Phase Kinase-Associated Proteins; D045162:Thiazolidinediones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077288:Troglitazone