Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
Cancer Res. 2010 Dec 1;70(23):9730-41. doi: 10.1158/0008-5472.CAN-10-1882. Epub 2010 Nov 23.
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 downregulation.
ErbB3 结合蛋白 Ebp1 与多种人类癌症有关。Ebp1 包括 2 种异构体，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 异构体具有转化能力，并促进人神经胶质瘤（GBM）中的细胞生长、集落形成和侵袭。在 GBM 细胞中过表达 p48 促进了致瘤作用，并增强了小鼠异种移植模型中的肿瘤生长。与周围正常组织或低级别肿瘤相比，人类 GBM 组织中 p48 的水平升高。值得注意的是，p48 水平与 GBM 患者的预后不良呈负相关。我们确定 p48 与 p53 E3 连接酶 HDM2 结合，增强了 HDM2-p53 结合，从而促进了 p53 的多泛素化和降解，降低了稳定状态下 p53 的水平和活性。总之，我们的研究结果表明，p48 通过与 HDM2 的相互作用促进神经胶质瘤的发生，从而下调 p53，发挥癌基因的作用。
