Negative Regulation of p53 by the Long Isoform of ErbB3 Binding Protein Ebp1 in Brain Tumors
Negative Regulation of p53 by the Long Isoform of ErbB3 Binding Protein Ebp1 in Brain Tumors
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DOI：
10.1158/0008-5472.can-10-1882
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Ahn, Jee-Yin
中科院分区：
文献类型：
--
作者：
Kim, Chung Kwon;Nguyen, Truong L. X.;Ahn, Jee-Yin
ErbB 3结合蛋白Ebp 1与许多人类癌症有关。Ebp 1包括两种亚型p48和p42，它们表现出不同的细胞活性。在这里，我们表明，较大的p48亚型是转化，它促进细胞生长，克隆形成，并在人类胶质母细胞瘤（GBM）的入侵。在小鼠异种移植模型中，GBM细胞中P48过表达促进肿瘤发生并增强肿瘤生长。与周围正常组织或低级别肿瘤相比，人GBM组织显示p48水平升高。值得注意的是，p48水平与GBM患者的不良预后呈负相关。我们确定p48与p53 E3连接酶HDM 2结合，增强HDM 2-p53结合，从而促进p53多聚泛素化和降解，降低稳态p53水平和活性。总之，我们的研究结果表明，p48作为一个癌基因的功能，促进胶质瘤的致瘤性通过与HDM 2的相互作用，有助于p53下调。Cancer Res; 70（23）; 9730-41. (C)2010年AACR。
The ErbB3 binding protein Ebp1 has been implicated in a number of human cancers. Ebp1 includes 2 isoforms, p48 and p42, that exhibit different cellular activities. Here we show that the larger p48 isoform is transforming and that it promotes cell growth, clonogenicity, and invasion in human glioblastoma (GBM). P48 overexpression in GBM cells facilitated tumorigenesis and enhanced tumor growth in mouse xenograft models. Human GBM tissues displayed elevated levels of p48 compared with surrounding normal tissues or low-grade tumors. Notably, p48 levels were inversely correlated with poor prognosis in GBM patients. We determined that p48 binds to the p53 E3 ligase HDM2, enhancing HDM2-p53 association and thereby promoting p53 polyubiquitination and degradation to reduce steady-state p53 levels and activity. Together, our findings suggest that p48 functions as an oncogene by promoting glioma tumorigenicity via interactions with HDM2 that contribute to p53 dow-nregulation. Cancer Res; 70(23); 9730-41. (C) 2010 AACR.