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Vol. 20, Issue 3, 757-768, February 1, 2009

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Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Zhixue Liu^*,, Sang-Muk Oh^*,, Masashi Okada^*, Xia Liu^*, Dongmei Cheng, Junmin Peng, Daniel J. Brat^*, Shi-yong Sun, Wei Zhou, Wei Gu^||, and Keqiang Ye^*

*Department of Pathology and Laboratory Medicine, Department of Human Genetics, and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322; and ^||Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032

Submitted September 30, 2008; Revised October 27, 2008; Accepted November 18, 2008
Monitoring Editor: Jonathan Chernoff

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.

These authors contributed equally to this work.

Address correspondence to: Keqiang Ye (kye{at}emory.edu)