Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor
Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor
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DOI：
10.1091/mbc.e08-09-0983
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发表时间：
2009-02-01
影响因子：
3.3
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Liu, Zhixue;Oh, Sang-Muk;Ye, Keqiang
人类Bre1是H2B单泛素化的E3连接酶，与p53结合并增强激活剂依赖性转录。Ebp1是一种ErbB3受体结合蛋白，可抑制细胞增殖并起到肿瘤抑制作用。在这里，我们发现hBre1作为Ebp1肿瘤抑制因子的E3泛素连接酶，并促进其多泛素化和降解。Ebp1在癌细胞中多泛素化，受其磷酸化调节。我们发现hBre1作为Ebp1的E3连接酶并增加其多泛素化。hBre1的缺失阻断了Ebp1的多泛素化并提高了其蛋白水平，从而阻止了癌症的扩散。hBre1结合Ebp1并抑制其对E2F-1的抑制作用。此外，Ebp1蛋白水平在人类癌症中显著降低。它在原发性胶质瘤的细胞核中被强烈磷酸化并定位，与hBre1亚细胞驻留相关。因此，hBre1通过介导Ebp1的多泛素化和降解来抑制Ebp1的抑瘤活性。
Human Bre1, an E3 ligase for H2B monoubiquitination, binds p53 and enhances activator-dependent transcription. Ebp1, an ErbB3 receptor-binding protein, inhibits cell proliferation and acts as a tumor suppressor. Here, we show that hBre1 acts as an E3 ubiquitin ligase for Ebp1 tumor suppressor and promotes its polyubiquitination and degradation. Ebp1 is polyubiquitinated in cancer cells, which is regulated by its phosphorylation. We identified hBre1 acting as an E3 ligase for Ebp1 and increasing its polyubiquitination. Depletion of hBre1 blocks Ebp1's polyubiquitination and elevates its protein level, preventing cancer proliferation. hBre1 binds Ebp1 and suppresses its repressive effect on E2F-1. Moreover, Ebp1 protein level is substantially diminished in human cancers. It is robustly phosphorylated and localized in the nucleus of primary gliomas, correlating with hBre1 subcellular residency. Thus, hBre1 inhibits Ebp1's tumor suppressive activity through mediating its polyubiquitination and degradation.