Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

• Type of Material: Article
• Authors: Zhixue Liu, Emory University; Sang-Muk Oh, Emory University; Masashi Okada, Emory University; Xia Liu, Emory University; Dongmei Cheng, Emory University; Junmin Peng, Emory University; Daniel J Brat, Emory University; Shi-yong Sun, Emory University; Wei Zhou, Emory University; Wei Gu, Columbia University; Keqiang Ye, Emory University
• Language: English
• Date: 2009-02-01
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2009 by The American Society for Cell Biology
• Final Published Version (URL): http://www.molbiolcell.org/content/20/3/757
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 20
• Issue: 3
• Start Page: 757
• End Page: 768
• Grant/Funding Information: This work is supported by National Institute of Health grant R01, NS-045627 (to K.Y.)
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology; Biology, Genetics

Abstract

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.