The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling
The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling
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DOI：
10.1038/cr.2011.103
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发表时间：
2011-08-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Hong-yang
中科院分区：
文献类型：
--
作者：
Dong, Li-wei;Yang, Guang-zhen;Wang, Hong-yang
p28（GANK）（也称为PSMD 10或Gankyrin）是一种在肝细胞癌（HCC）中高度表达的新型癌蛋白。通过与各种蛋白质的相互作用，p28（GANK）介导肿瘤抑制蛋白Rb和p53的降解。尽管有报道称p53下调β-连环蛋白，但p28（GANK）是否参与β-连环蛋白的调节仍不确定。在这里，我们报告说，生长因子和Ras上调p28（GANK）的表达，通过激活磷酸肌醇3-激酶-AKT途径。p28（GANK）表达的上调随后增强了β-连环蛋白的转录活性。在p53缺陷细胞中观察到这种效应，表明p28（GANK）介导的β-连环蛋白激活的p53非依赖性机制。p28（GANK）过表达也降低了E-钙粘蛋白蛋白水平，导致游离β-连环蛋白从钙粘蛋白结合池释放到细胞质中的增加。有趣的是，p28（GANK）的外源性表达导致内源性蛋白质的表达升高。我们还观察到β-catenin和c-Myc都是p28（GANK）的转录激活因子，并且p28（GANK）过表达与原发性人HCC中c-Myc、cyclin D1和β-catenin激活之间存在相关性。总之，这些结果表明，p28（GANK）表达受到涉及β-连环蛋白的正反馈回路的调节，这可能在肿瘤发生和HCC的进展中起关键作用。
p28(GANK) (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28(GANK) mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate beta-catenin, whether p28(GANK) is involved in the regulation of beta-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28(GANK) expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28(GANK) expression subsequently enhanced the transcription activity of beta-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28(GANK)-mediated activation of beta-catenin. p28(GANK) overexpression also reduced E-cadherin protein levels, leading to increased release of free beta-catenin into the cytoplasm from the cadherin- bound pool. Interestingly, exogenous expression of p28(GANK) resulted in elevated expression of the endogenous protein. We also observed that both beta-catenin and c-Myc were transcriptional activators of p28(GANK), and a correlation between p28(GANK) overexpression and c-Myc, cyclin D1 and beta-catenin activation in primary human HCC. Together, these results suggest that p28(GANK) expression is regulated by a positive feedback loop involving beta-catenin, which may play a critical role in tumorigenesis and the progression of HCC.