Human BRE1 is an E3 ubiquitin ligase for Ebp1 tumor suppressor.
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.
Liu
Zhixue
Z
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Oh
Sang-Muk
SM
Okada
Masashi
M
Liu
Xia
X
Cheng
Dongmei
D
Peng
Junmin
J
Brat
Daniel J
DJ
Sun
Shi-yong
SY
Zhou
Wei
W
Gu
Wei
W
Ye
Keqiang
K
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D049109:Cell Proliferation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C101633:PA2G4 protein, human; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; D010768:Phosphoserine; C413363:RNF40 protein, human; D044767:Ubiquitin-Protein Ligases