Skp2 deficiency inhibits chemical skin tumorigenesis independent of p27(Kip1) accumulation.
Skp2 deficiency inhibits chemical skin tumorigenesis independent of p27(Kip1) accumulation.
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DOI：
10.1016/j.ajpath.2013.01.016
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发表时间：
2013-05
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影响因子：
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通讯作者：
Christopher Sistrunk;Sun Hye Kim;Xian Wang;Sung Hyun Lee;Yongbaek Kim;Everardo Macias;M. Rodriguez-Puebla
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文献类型：
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作者：
Christopher Sistrunk;Sun Hye Kim;Xian Wang;Sung Hyun Lee;Yongbaek Kim;Everardo Macias;M. Rodriguez-Puebla
S期激酶相关蛋白2（Skp 2）作为Skp-Cullin-F-box复合物的受体成分发挥功能，并参与几种细胞周期调节因子如p21 Cip 1、p27 Kip 1、p57 Kip 2和细胞周期蛋白E的降解。在人类和实验性肿瘤中的大量研究已经证明p27 Kip 1水平低和Skp 2表达升高。然而，Skp 2和p27 Kip 1的负相关性与肿瘤发生之间的直接关联尚未得到证实。在此，我们提供的证据表明，皮肤肿瘤的发生是抑制在Skp 2 −/−小鼠。对小鼠角质形成细胞的分析表明，Skp 2 −/−表皮中p27 Kip 1水平的增加导致细胞增殖减少，而Skp 2 −/−/p27−/−复合小鼠表皮中的细胞增殖减少。相比之下，我们确定p27 Kip 1缺陷不会推翻Skp 2 −/−小鼠经历的皮肤肿瘤发生减少。此外，Skp 2 −/−表皮表现出p53-辅因子CBP/p300的积累，这与毛囊中细胞凋亡的增加和皮肤肿瘤发生的减少有关。我们的结论是，p27 Kip 1积累是负责观察到的发育不全的正常组织ofSkp 2 −/−小鼠，但没有一个优势功能，减少皮肤肿瘤的发生。
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 p21Cip1, p27Kip1, p57Kip2, and cyclin E. Numerous studies in human and experimental tumors have demonstrated low p27Kip1levels and elevated Skp2 expression. However, a direct association between the inverse correlation of Skp2 and p27Kip1with tumorigenesis has not been demonstrated. Herein, we provide evidence that skin tumorigenesis is inhibited inSkp2−/−mice. An analysis of mouse keratinocytes indicates that increased p27Kip1levels inSkp2−/−epidermis cause reduced cell proliferation that is alleviated in the epidermis fromSkp2−/−/p27−/−compound mice. In contrast, we establish that a p27Kip1deficiency does not overturn the reduced skin tumorigenesis experienced bySkp2−/−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 p27Kip1accumulation is responsible for the hypoplasia observed in normal tissues ofSkp2−/−mice but does not have a preponderant function in reducing skin tumorigenesis.