title: Skp2 is necessary for Myc-induced keratinocyte proliferation but dispensable for Myc oncogenic activity in the oral epithelium.
abstract: The proto-oncogene c-Myc encodes a transcription factor that is implicated in the regulation of cellular proliferation, differentiation, and apoptosis. Myc accelerates the rate of cell proliferation, at least in part, through its ability to down-regulate the expression of the cell cycle inhibitor p27(Kip1). Moreover, p27(Kip1) protein levels are regulated by ubiquitin-mediated turnover, leading to destruction by the E3 ubiquitin ligase SCF(Skp2). Therefore, we hypothesize that a lack of Skp2 expression should lead to increased p27(Kip1) levels and further inhibition of Myc-mediated proliferation and tumorigenesis. Myc expression in epithelial tissues of transgenic mice (K5-Myc) led to increased keratinocyte proliferation and the development of spontaneous tumors within the oral cavity. We generated K5-Myc-transgenic mice in an Skp2-null background. Consistent with our hypothesis, we found that Myc-mediated keratinocyte hyperproliferation was abolished by the loss of Skp2. However, Skp2 ablation did not affect Myc-driven tumorigenesis because the incidence, latency, and degree of differentiation of oral tumors were identical between K5-Myc/Skp2(+/+) and K5-Myc/Skp2(-/-) mice. Altogether, these findings suggest that Skp2 and p27(Kip1) are critical for Myc-driven keratinocyte proliferation; however, Myc-mediated tumorigenesis in the oral epithelium is independent of the Skp2-p27(Kip1) axis.
authors.affiliation: Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sistrunk
authors.forename: Everardo
authors.initials: E
authors.lastname: Macias
authors.forename: Keiichi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Yongbaek
authors.initials: Y
authors.lastname: Kim
authors.forename: Marcelo L
authors.initials: ML
authors.lastname: Rodriguez-Puebla
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009055:Mouth / Q000473:pathology*; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011230:Precancerous Conditions / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc; D044786:S-Phase Kinase-Associated Proteins