Skp2 is necessary for Myc-induced keratinocyte proliferation but dispensable for Myc oncogenic activity in the oral epithelium.
Skp2 is necessary for Myc-induced keratinocyte proliferation but dispensable for Myc oncogenic activity in the oral epithelium.
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DOI：
10.1016/j.ajpath.2011.02.034
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
Christopher Sistrunk;Everardo Macias;K. Nakayama;Yongbaek Kim;M. Rodriguez-Puebla
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作者：
Christopher Sistrunk;Everardo Macias;K. Nakayama;Yongbaek Kim;M. Rodriguez-Puebla
原癌基因- mycenc编码一种转录因子，参与细胞增殖、分化和凋亡的调控。myc通过下调细胞周期抑制剂p27Kip1的表达，至少在一定程度上加快了细胞增殖的速度。此外，p27kip1蛋白水平受泛素介导的转换调节，导致E3泛素连接酶SCFSkp2的破坏。因此，我们假设Skp2表达缺失可能导致p27kip1水平升高，并进一步抑制myc介导的增殖和肿瘤发生。转基因小鼠上皮组织中myc的表达（K5-Myc）导致角化细胞增殖增加和口腔内自发肿瘤的发生。我们在skp2缺失的背景下产生了k5 - myc转基因小鼠。与我们的假设一致，我们发现myc介导的角化细胞过度增生被Skp2的缺失所消除。然而，Skp2消融并不影响myc驱动的肿瘤发生，因为K5-Myc/Skp2+/+和K5-Myc/Skp2−/−小鼠的口腔肿瘤的发生率、潜伏期和分化程度是相同的。总之，这些发现表明Skp2和p27kip1是关键的formyc驱动的角化细胞增殖；然而，myc介导的口腔上皮肿瘤发生不依赖于skp2 - p27kip1轴。
The proto-oncogenec-Mycencodes a transcription factor that is implicated in the regulation of cellular proliferation, differentiation, and apoptosis.Mycaccelerates the rate of cell proliferation, at least in part, through its ability to down-regulate the expression of the cell cycle inhibitor p27Kip1. Moreover, p27Kip1protein levels are regulated by ubiquitin-mediated turnover, leading to destruction by the E3 ubiquitin ligase SCFSkp2. Therefore, we hypothesize that a lack of Skp2 expression should lead to increased p27Kip1levels and further inhibition ofMyc-mediated proliferation and tumorigenesis.Mycexpression 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 thatMyc-mediated keratinocyte hyperproliferation was abolished by the loss of Skp2. However, Skp2 ablation did not affectMyc-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 p27Kip1are critical forMyc-driven keratinocyte proliferation; however,Myc-mediated tumorigenesis in the oral epithelium is independent of the Skp2-p27Kip1axis.