Modification of p27 With O-Linked N-Acetylglucosamine Regulates Cell Proliferation in Hepatocellular Carcinoma
Modification of p27 With O-Linked N-Acetylglucosamine Regulates Cell Proliferation in Hepatocellular Carcinoma
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O-连接 N-乙酰氨基葡萄糖修饰 p27 可调节肝细胞癌中的细胞增殖
DOI：
10.1002/mc.22490
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发表时间：
2017
影响因子：
4.6
通讯作者：
Aiguo Shen
中科院分区：
文献类型：
--
作者：
Huiyuan Qiu;Fang Liu;Tao Tao;Dongmei Zhang;Xiaojuan Liu;Guizhou Zhu;Zhiwei Xu;Runzhou Ni;Aiguo Shen
肿瘤抑制因子p27是细胞周期蛋白依赖的蛋白抑制蛋白(CKIs)中Cip/Kip家族的一员，控制着抗增殖事件。在HEK293T和肝癌细胞系中存在O-GlcNAc与p27的翻译后加成，我们根据Q-TOF谱确定Ser2、Ser106、Ser110、Thr157和Thr198为p27的糖基化位点。免疫沉淀分析表明，Ser2是O-GlcN酰化的，这种修饰与Ser10处p27的磷酸化增加有关，最终导致p27在细胞质中聚集并增加p27泛素化。此外，Ser2的O-GlcN酰化通过促进p27的核输出来抑制Cyclin/.CDK复合体-p27的相互作用，从而促进细胞周期的进展。当p27的Ser2被ALA取代时，细胞增殖受到负调控。此外，对肝细胞癌组织和相应的非肿瘤组织进行免疫印迹和免疫组织化学分析，我们发现O-GlcNacylated p27与肝细胞癌的细胞增殖有关。总之，我们的结果表明，O-GlcN酰化和p27磷酸化之间的动态相互作用协调和调节了肝细胞癌中的细胞增殖
The tumor suppressor p27, which is a member of the Cip/Kip family of Cyclin-dependent kinase inhibitory proteins.(CKIs), controls anti-proliferative events. The post-translational addition of O-GlcNAc to p27 occurs in HEK293T and HCC.(hepatocellular carcinoma) cell lines, and we identifi ed Ser2, Ser106, Ser110, Thr157, and Thr198 as the glycosylation sites.of p27 based on the Q-TOF spectrum. Here, immunoprecipitation analysis showed that Ser2 was O-GlcNAcylated and that.this modifi cation was associated with the increased phosphorylation of p27 at Ser10, ultimately resulting in p27.accumulation in the cytoplasm and increased p27 ubiquitination. In addition, O-GlcNAcylation at Ser2 suppressed Cyclin/.CDK complex-p27 interactions by promoting the nuclear export of p27, thus facilitating cell cycle progression. Cell.proliferation was negatively regulated when Ser2 of p27 was replaced with Ala. Furthermore, western blot and.immunohistochemical analyses of HCC tissues and their corresponding nontumorous tissues were performed, and we.found that O-GlcNAcylated p27 correlated with cell proliferation in HCC. Together, our results indicate that the dynamic.interplay between O-GlcNAcylation and p27 phosphorylation coordinates and regulates cell proliferation in.hepatocellular carcinoma