title: Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP.
abstract: We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen-ERα (oestrogen receptor α) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen-ERα signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen-induced transcriptional up-regulation as well as UPP (ubiquitin-proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERα target gene products. 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 oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen-ERα signalling and thus implicate ATBF1 in oestrogen-dependent breast development and carcinogenesis.
authors.affiliation: Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer Institute, Emory University, 1365-C Clifton Road, Atlanta, GA 30322, USA. dxueyua@emory.edu
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Dong
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Fu
authors.forename: Songqing
authors.initials: S
authors.lastname: Fan
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
mesh_terms: D045744:Cell Line, Tumor; D004967:Estrogens / Q000502:physiology*; D005260:Female; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D059748:Proteolysis; D014157:Transcription Factors / Q000096:biosynthesis*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
chemical_list: D004967:Estrogens; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C071660:ZFHX3 protein, human; C084523:TRIM25 protein, human; D044767:Ubiquitin-Protein Ligases