Abstract
p28GANK (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28GANK mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate β-catenin, whether p28GANK is involved in the regulation of β-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28GANK expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28GANK expression subsequently enhanced the transcription activity of β-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28GANK-mediated activation of β-catenin. p28GANK 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 p28GANK resulted in elevated expression of the endogenous protein. We also observed that both β-catenin and c-Myc were transcriptional activators of p28GANK, and a correlation between p28GANK overexpression and c-Myc, cyclin D1 and β-catenin activation in primary human HCC. Together, these results suggest that p28GANK expression is regulated by a positive feedback loop involving β-catenin, which may play a critical role in tumorigenesis and the progression of HCC.
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Acknowledgements
We thank Dr Claudia Cosentino and Dr Jin Q Cheng for kindly providing some of the plasmids. We are also grateful to Dr David Blake and Dr Xiaoni Kong (School of Public Health, Johns Hopkins University, Baltimore, MD) for helpful discussion. Research was supported by grants from the Funds for Creative Research Groups of China (30921006), the State Key Project for Liver Cancer (2008ZX10002), the State Key Laboratory of Oncogenes and Related Genes (91-10-02, 91-10-03), the National Natural Science Foundation of China (81001075, 81071778).
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Dong, Lw., Yang, Gz., Pan, Yf. et al. The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling. Cell Res 21, 1248–1261 (2011). https://doi.org/10.1038/cr.2011.103
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DOI: https://doi.org/10.1038/cr.2011.103
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