title: Skp2 deficiency inhibits chemical skin tumorigenesis independent of p27(Kip1) accumulation.
abstract: S-phase kinase-associated protein 2 (Skp2) functions as the receptor component of the Skp-Cullin-F-box complex and is implicated in the degradation of several cell cycle regulators, such as p21(Cip1), p27(Kip1), p57(Kip2), and cyclin E. Numerous studies in human and experimental tumors have demonstrated low p27(Kip1) levels and elevated Skp2 expression. However, a direct association between the inverse correlation of Skp2 and p27(Kip1) with tumorigenesis has not been demonstrated. Herein, we provide evidence that skin tumorigenesis is inhibited in Skp2(-/-) mice. An analysis of mouse keratinocytes indicates that increased p27(Kip1) levels in Skp2(-/-) epidermis cause reduced cell proliferation that is alleviated in the epidermis from Skp2(-/-)/p27(-/-) compound mice. In contrast, we establish that a p27(Kip1) deficiency does not overturn the reduced skin tumorigenesis experienced by Skp2(-/-) mice. In addition, Skp2(-/-) epidermis exhibits an accumulation of p53-cofactor CBP/p300 that is associated with elevated apoptosis in hair follicles and decreased skin tumorigenesis. We conclude that p27(Kip1) accumulation is responsible for the hypoplasia observed in normal tissues of Skp2(-/-) mice but does not have a preponderant function in reducing skin tumorigenesis.
authors.affiliation: Department of Molecular Biomedical Sciences and the Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sistrunk
authors.forename: Sun Hye
authors.initials: SH
authors.lastname: Kim
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Yongbaek
authors.initials: Y
authors.lastname: Kim
authors.forename: Everardo
authors.initials: E
authors.lastname: Macias
authors.forename: Marcelo L
authors.initials: ML
authors.lastname: Rodriguez-Puebla
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010212:Papilloma / Q000378:metabolism / Q000473:pathology; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism
chemical_list: D044786:S-Phase Kinase-Associated Proteins; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27