ORIGINAL ARTICLE

Cell Research (2009): 1243-1257
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p28^GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity

Rong-Yang Dai^1,2,*, Yao Chen^2,*, Jing Fu², Li-Wei Dong², Yi-Bin Ren², Guang-Zhen Yang², You-Wen Qian², Jie Cao², Shan-Hua Tang², Sheng-Li Yang¹ and Hong-Yang Wang^1,2

Correspondence: Hong-Yang Wang, Tel: +86-21-81875361; Fax: +86-21-65566851 E-mail: hywangk@vip.sina.com *These two authors contributed equally to this work.

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It has been shown that oncoprotein p28^GANK, which is consistently overexpressed in human hepatocellular carcinoma (HCC), plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28^GANK inhibits apoptosis in HCC cells induced by the endoplasmic reticulum (ER) stress. During ER stress, p28^GANK enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell's ability to cope with the stress conditions. Furthermore, p28^GANK upregulates glucose-regulated protein 78 (GRP78), a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28^GANK increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B (NF-κB) activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28^GANK inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28^GANK has potential implications for HCC progression under the ER stress conditions.

Cell Research (2009) 19:1243–1257. doi: 10.1038/cr.2009.104; published online 8 September 2009

Keywords: p28^GANK, ER stress, UPR, GRP78, apoptosis