Volume 21 Issue 8, August 2011: 1248-1261
ORIGINAL ARTICLES
The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling
Li-wei Dong1,*, Guang-zhen Yang1,*, Yu-fei Pan1,*, Yao Chen1, Ye-xiong Tan1, Rong-yang Dai1, Yi-bin Ren1, Jing Fu1 and Hong-yang Wang1,2
1International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
2State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
Correspondence: Hong-yang Wang,(hywangk@vip.sina.com)
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 β-catenin, whether p28
GANK is involved in the regulation of β-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 β-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28
GANK-mediated activation of β-catenin. p28
GANK 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 p28
GANK resulted in elevated expression of the endogenous protein. We also observed that both β-catenin and c-Myc were transcriptional activators of p28
GANK, and a correlation between p28
GANK overexpression and c-Myc, cyclin D1 and β-catenin activation in primary human HCC. Together, these results suggest that p28
GANK expression is regulated by a positive feedback loop involving β-catenin, which may play a critical role in tumorigenesis and the progression of HCC.
Cell Research (2011) 21:1248-1261. doi:10.1038/cr.2011.103; published online 21 June 2011
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