MIF4G domain containing protein regulates cell cycle and hepatic carcinogenesis by antagonizing CDK2-dependent p27 stability
MIF4G domain containing protein regulates cell cycle and hepatic carcinogenesis by antagonizing CDK2-dependent p27 stability
复制标题
含有 MIF4G 结构域的蛋白通过拮抗 CDK2 依赖性 p27 稳定性来调节细胞周期和肝癌发生
DOI：
10.1038/onc.2013.536
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发表时间：
2015-01-08
期刊：
影响因子：
8
通讯作者：
Shen, A.
中科院分区：
文献类型：
--
作者：
Wan, C.;Hou, S.;Shen, A.
CDK抑制剂p27 kip 1在细胞周期调控和癌症进展中起着至关重要的作用。通过酵母双杂交筛选，我们鉴定了MIF 4G结构域蛋白（MIF 4GD）作为p27的新结合伴侣。使用免疫沉淀和谷胱甘肽S-转移酶（GST）下拉测定验证MIF 4GD和p27的关联。与MIF 4GD的相互作用导致肝细胞癌（HCC）细胞中细胞核和细胞质中p27的稳定，这是由于CDK 2在苏氨酸187处抑制p27的磷酸化。血清刺激同时降低MIF 4GD和p27的水平。此外，MIF 4GD过表达导致p27水平增加和细胞增殖减少，而MIF 4GD敲低促进细胞周期进展，细胞中p27水平降低。此外，MIF 4GD的过表达减少了集落形成并抑制了裸鼠中异种移植瘤的生长。最后，我们发现，与非癌组织相比，MIF 4GD和p27在HCC组织中的表达水平较低，并且MIF 4GD和p27的低表达水平与HCC患者的预后显著较差相关。我们的研究结果表明，MIF 4GD是一个潜在的调节p27依赖的细胞增殖在肝癌。这些发现为通过靶向MIF 4GD-p27相互作用开发潜在的HCC治疗提供了合理的框架。
The CDK inhibitor p27 kip1 plays crucial roles in cell cycle regulation and cancer progression. Through yeast two-hybrid screening, we identified MIF4G domain containing protein (MIF4GD) as a novel binding partner for p27. The association of MIF4GD and p27 was verified using immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Interaction with MIF4GD led to the stabilization of p27 both in the nucleus and in the cytoplasm in hepatocellular carcinoma (HCC) cells as a result of suppressed phosphorylation of p27 by CDK2 at threonine187. Serum stimulation decreased the levels of MIF4GD and p27 simultaneously. In addition, MIF4GD overexpression resulted in increased p27 levels and reduced cell proliferation, while knockdown of MIF4GD promoted cell cycle progression with decreased p27 levels in cells. Furthermore, overexpression of MIF4GD reduced colony formation and inhibited xenograft tumor growth in nude mice. Finally, we found that both MIF4GD and p27 were expressed at low levels in HCC tissues compared to non-cancerous tissues, and that low expression levels of MIF4GD and p27 were associated with significantly worse prognosis in HCC patients. Our results suggest that MIF4GD is a potential regulator of p27-dependent cell proliferation in HCC. These findings provide a rational framework for the development of potential HCC therapy by targeting the MIF4GD–p27 interaction.