title: Skp2 promotes adipocyte differentiation via a p27Kip1-independent mechanism in primary mouse embryonic fibroblasts.
abstract: 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.
authors.affiliation: Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Okada
authors.forename: Tamon
authors.initials: T
authors.lastname: Sakai
authors.forename: Takehiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Mimi
authors.initials: M
authors.lastname: Tamamori-Adachi
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Kitajima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Eijiro
authors.initials: E
authors.lastname: Watanabe
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: 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
chemical_list: C493961:Cdkn1b protein, mouse; D002839:Chromans; D044786:S-Phase Kinase-Associated Proteins; D045162:Thiazolidinediones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077288:Troglitazone