Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate.
Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate.
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发表时间：
2003-04
期刊：
影响因子：
11.2
通讯作者：
Eun-Hee Shim;Linda K. Johnson;H. Noh;Y. Kim;Hong Sun;C. Zeiss;Hui Zhang
中科院分区：
文献类型：
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作者：
Eun-Hee Shim;Linda K. Johnson;H. Noh;Y. Kim;Hong Sun;C. Zeiss;Hui Zhang
细胞周期蛋白依赖性激酶抑制剂 p27 (Kip1) 的低表达或缺失表达是前列腺癌和其他人类癌症的极佳恶性标志物。 p27(Kip1) 的水平主要由泛素 E3 连接酶 SCF(SKP2) 通过泛素依赖性蛋白水解来调节。在许多癌症中，F-box 蛋白 SKP2 的表达与 p27 呈负相关。为了确定 SCF(SKP2) 在增殖和肿瘤发生中的作用，我们建立了在前列腺中特异性表达 SKP2 的转基因小鼠系。 SKP2的非计划表达促进显着的过度增殖，导致前列腺增生、不典型增生和低度癌。与其在 p27 蛋白水解中的关键作用一致，SKP2 表达导致转基因动物前列腺中 p27 的显着下调。免疫组织学染色表明，SKP2 表达仅限于增生/发育异常区域，并且转基因动物的导管上皮中 SKP2 和 p27 表达之间存在负相关关系。转基因小鼠的前列腺还表现出高水平的增殖和有丝分裂标记物，例如 Ki67 和细胞周期蛋白 B1。我们的数据表明，SKP2 在小鼠前列腺中充当癌蛋白，可能是通过其作为泛素依赖性 p27 降解的限制因素的功能而发挥作用。
Low or absent expression of the cyclin-dependent kinase inhibitor p27(Kip1) serves as an excellent malignant marker for prostate and other human cancers. The level of p27(Kip1) is regulated primarily by the ubiquitin E3 ligase SCF(SKP2) through ubiquitin-dependent proteolysis. Expression of the F-box protein SKP2 is inversely correlated with p27 in many cancers. To determine the role of SCF(SKP2) in proliferation and tumorigenesis, we established transgenic mouse lines that specifically expressed SKP2 in the prostate gland. Unscheduled expression of SKP2 promoted marked overproliferation, resulting in hyperplasia, dysplasia, and low-grade carcinoma in the prostate gland. Consistent with its critical role in p27 proteolysis, SKP2 expression caused significant down-regulation of p27 in prostate glands from transgenic animals. Immunohistological staining indicated that SKP2 expression is restricted to the hyperplastic/dysplastic regions and that there is an inverse relationship between SKP2 and p27 expression in the ductal epithelium in transgenic animals. The prostate glands from transgenic mice also exhibited high levels of proliferative and mitotic markers such as Ki67 and cyclin B1. Our data suggest that SKP2 acts as an oncoprotein in the mouse prostate gland, probably through its function as a limiting factor for ubiquitin-dependent degradation of p27.