title: Molecular mechanism of WW-domain binding protein-2 coactivation function in estrogen receptor signaling.
abstract: The link between breast cancer and estrogen receptor (ER) is well established. The ER is a hormone-inducible transcription factor that, upon binding to its ligand, regulates the expression of a variety of genes mainly involved in cell proliferation and differentiation. Coactivators are proteins recruited by the hormone-activated receptor, which allow or enhance the ER transactivation functions by acting as chromatin remodeling enzymes or adaptors between ER and the transcriptional machinery. Our laboratory has previously identified the WW-domain binding protein-2 (WBP-2) as a bona fide coactivator of ER. However, the molecular mechanism underlying WBP-2 coactivation function was not clear yet. In this study, we explore and identify the mechanism by which WBP-2 acts as coactivator of ER. Our data show that WBP-2 is involved in the regulation of ER target genes, and its expression is required for the proper expression of some ER target genes. To clarify the molecular mechanism by which WBP-2 regulates ER function, we performed chromatin immunoprecipitation assays. We demonstrate here that WBP-2 binds to the ER target gene promoter pS2 promoter and is required for the binding of the phosphorylated form of RNA polymerase II (associated with active transcription/elongation) to the same promoter. Furthermore, we also show that WBP-2 is essential for the recruitment of the histone acetyl transferase p300, an important chromatin modifier enzyme and for histone acetylation at the same target region. Collectively, our data indicate that WBP-2 enhances ER transactivation function at certain genes by facilitating the recruitment and/or the stabilization of a histone modifier enzyme that favors a relaxed chromatin structure, permissive of transcription.
authors.affiliation: Braman Family Breast Cancer Institute / Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Buffa
authors.forename: Ali M
authors.initials: AM
authors.lastname: Saeed
authors.forename: Zafar
authors.initials: Z
authors.lastname: Nawaz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D006801:Humans; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D015534:Trans-Activators; C106908:WBP2 protein, human