Estrogen causes ATBF1 protein degradation through the estrogen-responsive E3 ubiquitin ligase EFP

• Type of Material: Article
• Authors: Xueyuan Dong, Emory University; Xiaoying Fu, Emory University; Songqing Fan, Emory University; Peng Guo, Emory University; Dan Su, Emory University; Xiaodong Sun, Emory University; Jin-Tang Dong, Emory University
• Language: English
• Date: 2012-06-15
• Publisher: Portland Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © The Authors Journal compilation © 2012 Biochemical Society
• Final Published Version (URL): http://www.biochemj.org/bj/444/0581/bj4440581.htm
• Title of Journal or Parent Work: Biochemical Journal
• ISSN: 0264-6021
• Volume: 444
• Issue: 3
• Start Page: 581
• End Page: 590
• Grant/Funding Information: This work was supported in part by Georgia Cancer Coalition award GCC130042 (to XY Dong), Robbins Scholar Award (to Dong XY) and NIH grant CA85560 (to JT Dong).
• Keywords: E3 ubiquitin ligase; Estrogen; EFP; Breast cancer; Protein degradation; ATBF1
• Research Categories: Health Sciences, Oncology

Abstract

We previously revealed that tumor suppressor ATBF1 formed an autoregulatory feedback loop with estrogen-ERα signaling to regulate estrogen-dependent cell proliferation in breast cancer cells. In this loop, ATBF1 inhibits the function of estrogen-ERα signaling while ATBF1 protein levels are fine-tuned by estrogen-induced transcriptional upregulation as well as ubiquitin proteasome pathway (UPP)-mediated protein degradation. Here we show that the estrogen-responsive finger protein (EFP) is an E3 ubiquitin ligase mediating estrogen-induced ATBF1 protein degradation. Knockdown increases but overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in estrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumors, due to both as directly-upregulated ERα target gene products, the levels of ATBF1 protein are positively correlated with the levels of EFP protein. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for estrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and estrogen-ERα signaling and thus implicate ATBF1 in estrogen-dependent breast development and carcinogenesis.