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首页> 外文期刊>Cell research. >The oncoprotein p28 GANK establishes a positive feedback loop in β-catenin signaling
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The oncoprotein p28 GANK establishes a positive feedback loop in β-catenin signaling

机译：癌蛋白p28 GANK在β-catenin信号传导中建立正反馈环

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p28supGANK/sup (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28supGANK/sup mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate β-catenin, whether p28supGANK/sup is involved in the regulation of β-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28supGANK/sup expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28supGANK/sup expression subsequently enhanced the transcription activity of β-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28supGANK/sup-mediated activation of β-catenin. p28supGANK/sup overexpression also reduced E-cadherin protein levels, leading to increased release of free β-catenin into the cytoplasm from the cadherin-bound pool. Interestingly, exogenous expression of p28supGANK/sup resulted in elevated expression of the endogenous protein. We also observed that both β-catenin and c-Myc were transcriptional activators of p28supGANK/sup, and a correlation between p28supGANK/sup overexpression and c-Myc, cyclin D1 and β-catenin activation in primary human HCC. Together, these results suggest that p28supGANK/sup expression is regulated by a positive feedback loop involving β-catenin, which may play a critical role in tumorigenesis and the progression of HCC.
机译：p28 GANK （也称为PSMD10或gankyrin）是一种新型癌蛋白，在肝细胞癌（HCC）中高度表达。通过与各种蛋白质的相互作用，p28 GANK 介导了肿瘤抑制蛋白Rb和p53的降解。尽管据报道p53下调了β-catenin，但尚不确定p28 GANK 是否参与β-catenin的调控。在这里，我们报道生长因子和Ras都通过磷酸肌醇3-激酶-AKT途径的激活来上调p28 GANK 的表达。 p28 GANK 表达的上调随后增强了β-catenin的转录活性。在缺乏p53的细胞中观察到了这种作用，这表明p28 GANK 介导的β-catenin活化机制与p53无关。 p28 GANK 的过表达也降低了E-钙粘蛋白的蛋白水平，导致游离的β-连环蛋白从钙粘蛋白结合池释放到细胞质中。有趣的是，p28 GANK 的外源表达导致内源蛋白表达升高。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c-Myc，cyclin D1和β-原发性人类肝癌中的连环蛋白激活。总之，这些结果表明，p28 GANK 的表达受涉及β-catenin的正反馈回路的调节，这可能在肿瘤发生和肝癌的发展中起关键作用。

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