SHARPIN促进乳腺癌细胞中p53的降解。
SHARPIN Facilitates p53 Degradation in Breast Cancer Cells.
作者信息
Yang Huijie, Yu Sifan, Wang Weilong, Li Xin, Hou Yingxiang, Liu Zhenhua, Shi Yuanyuan, Mu Kun, Niu Gang, Xu Juntao, Wang Hui, Zhu Jian, Zhuang Ting
机构信息
Research Center for Immunology, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China.
Research Center for Immunology, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Department of Renal Cancer and Melanoma, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.
出版信息
Neoplasia. 2017 Feb;19(2):84-92. doi: 10.1016/j.neo.2016.12.002. Epub 2017 Jan 5.
The ubiquitin binding protein SHAPRIN is highly expressed in human breast cancer, one of the most frequent female malignancies worldwide. Here, we perform SHARPIN depletion in breast cancer cells together with RNA sequencing. The global expression profiling showed p53 signaling as a potential SHARPIN target. SHARPIN depletion decreased cell proliferation, which effect could be rescue by p53 knocking down. Depletion SHARPIN significantly increases p53 protein level and its target genes in multiple breast cancer cell lines. Further experiment revealed that SHARPIN could facilitate p53 poly-ubiquitination and degradation in MDM2 dependent manner. Immuno-precipitation assay showed that SHARPIN associated with MDM2 and prolonged MDM2 protein stability. Analysis of public available database showed SHARPIN correlated with poor prognosis specifically in p53 wild-type breast cancer patients. Together, our finding revealed a novel modifier for p53/MDM2 complex and suggested SHARPIN as a promising target to restore p53 function in breast cancer.
泛素结合蛋白SHARPIN在人类乳腺癌中高表达，乳腺癌是全球女性中最常见的恶性肿瘤之一。在此，我们对乳腺癌细胞进行SHARPIN敲低并结合RNA测序。整体表达谱显示p53信号通路是SHARPIN的一个潜在靶点。SHARPIN敲低会降低细胞增殖，而这种效应可通过敲低p53来挽救。在多个乳腺癌细胞系中，敲低SHARPIN会显著增加p53蛋白水平及其靶基因。进一步实验表明，SHARPIN可通过依赖MDM2的方式促进p53的多聚泛素化和降解。免疫沉淀试验表明，SHARPIN与MDM2相关并延长了MDM2蛋白的稳定性。对公开可用数据库的分析表明，SHARPIN与预后不良相关，尤其在p53野生型乳腺癌患者中。总之，我们的发现揭示了一种p53/MDM2复合物的新型调节因子，并表明SHARPIN是恢复乳腺癌中p53功能的一个有前景的靶点。
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