p28GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity
p28GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity
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P28GANK 通过增强内质网适应能力来抑制内质网应激诱导的细胞死亡。
DOI：
10.1038/cr.2009.104
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发表时间：
2009-11-01
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：
Dai, Rong-Yang;Chen, Yao;Wang, Hong-Yang
研究表明，癌蛋白p28（GANK）在人肝细胞癌（HCC）中持续过表达，在HCC的肿瘤发生中起关键作用。然而，其潜在机制仍不清楚。在这里，我们证明了p28（GANK）抑制内质网（ER）应激诱导的肝癌细胞凋亡。在内质网应激期间，p28（GANK）增强未折叠蛋白反应，促进内质网从翻译抑制中恢复，从而促进细胞科普应激条件的能力。此外，p28（GANK）上调葡萄糖调节蛋白78（GRP 78），这是一种关键的ER伴侣蛋白，随后增强ER折叠能力并促进从ER应激中恢复。我们还证明，p28（GANK）增加p38丝裂原活化蛋白激酶和Akt磷酸化，并抑制核因子κ B（NF-κ B B）在ER应激下的活化，这反过来又有助于GRP 78上调。总之，我们的研究结果表明，p28（GANK）抑制ER应激诱导的肝癌细胞凋亡，至少部分，通过增强适应性反应和GRP 78的表达。我们认为p28（GANK）在ER应激条件下对HCC进展具有潜在意义。
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-kappa B) 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.