Skp2 Is Necessary for Myc-Induced Keratinocyte Proliferation but Dispensable for Myc Oncogenic Activity in the Oral Epithelium

被引:10
|
作者
Sistrunk, Christopher
Macias, Everardo
Nakayama, Keiichi [5 ]
Kim, Yongbaek [2 ,3 ]
Rodriguez-Puebla, Marcelo L. [1 ,4 ]
机构
[1] N Carolina State Univ, Coll Vet Med, Ctr Comparat Med & Translat Res, Raleigh, NC 27606 USA
[2] N Carolina State Univ, Dept Populat Hlth, Raleigh, NC 27606 USA
[3] N Carolina State Univ, Dept Pathobiol, Raleigh, NC 27606 USA
[4] N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27606 USA
[5] Kyushu Univ, Med Inst Bioregulat, Fukuoka 812, Japan
来源
AMERICAN JOURNAL OF PATHOLOGY | 2011年 / 178卷 / 06期
关键词
F-BOX PROTEIN; SQUAMOUS-CELL CARCINOMA; C-MYC; POOR-PROGNOSIS; INHIBITOR P27(KIP1); UBIQUITIN LIGASES; S-PHASE; EXPRESSION; DEGRADATION; TUMORIGENESIS;
D O I
10.1016/j.ajpath.2011.02.034
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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. (Am J Pathol 2011, 178:2470-2477; DOI: 10.1016/j.ajpath.2011.02.034)
引用
收藏
页码:2470 / 2477
页数:8
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