title: Estrogen receptor-α, RBCK1, and protein kinase C β 1 cooperate to regulate estrogen receptor-α gene expression.
abstract: Estrogen receptor α (ERα) is initially overexpressed in two-thirds of all breast cancers and is involved in its development and proliferation. We previously reported that the RanBP-type and C3HC4-type zinc finger containing 1 (RBCK1) interacts with the ERα promoter and that RBCK1 expression positively correlates with ERα levels, expression of ERα downstream target genes, and proliferation of breast cancer cells. Based on this, and that RBCK1 positively correlates with ERα expression in breast cancer samples, we propose RBCK1 as a potential therapeutic target in breast cancer acting as a modulator of ERα expression. To further explore this, the molecular mechanism by which RBCK1 regulates ERα expression has to be defined. Here, we show that ERα, RBCK1, and the RBCK1-interacting protein protein kinase C β 1 (PKCβ(I)) co-occupy a previously identified ERα binding region in the proximal ERα promoter. We describe a number of mechanistic details of this complex including that RBCK1 recruitment to the ERα promoter B is facilitated by ERα, which in turn facilitates PKCβ(I) recruitment and PKCβ(I)-dependent histone modifications. Furthermore, ERα regulation of its own mRNA expression is facilitated by RBCK1 recruitment, suggesting an ERα coactivator function of RBCK1. The interaction between RBCK1 and ERα was dependent on the E3 ubiquitin ligase domain of RBCK1 and the activating function-1 domain of ERα. The ligand-binding function of ERα does not influence the interaction with RBCK1. In summary, our data provide insight into the molecular mechanism by which ERα expression is modulated in breast cancer cells.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institute, NOVUM, S-14183 Huddinge, Stockholm, Sweden. nina.gustafsson@ki.se
authors.forename: Nina
authors.initials: N
authors.lastname: Gustafsson  Sheppard
authors.forename: Nina
authors.initials: N
authors.lastname: Heldring
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D014157:Transcription Factors; C504507:RBCK1 protein, human; D044767:Ubiquitin-Protein Ligases; D011493:Protein Kinase C; D064546:Protein Kinase C beta