title: Role of the nuclear receptor coactivator AIB1-Delta4 splice variant in the control of gene transcription.
abstract: The oncogene amplified in breast cancer 1 (AIB1) is a nuclear receptor coactivator that plays a major role in the progression of various cancers. We previously identified a splice variant of AIB1 called AIB1-Δ4 that is overexpressed in breast cancer. Using mass spectrometry, we define the translation initiation of AIB1-Δ4 at Met(224) of the full-length AIB1 sequence and have raised an antibody to a peptide representing the acetylated N terminus. We show that AIB1-Δ4 is predominantly localized in the cytoplasm, although leptomycin B nuclear export inhibition demonstrates that AIB1-Δ4 can enter and traffic through the nucleus. Our data indicate an import mechanism enhanced by other coactivators such as p300/CBP. We report that the endogenously and exogenously expressed AIB1-Δ4 is recruited as efficiently as full-length AIB1 to estrogen-response elements of genes, and it enhances estrogen-dependent transcription more effectively than AIB1. Expression of an N-terminal AIB1 protein fragment, which is lost in the AIB1-Δ4 isoform, potentiates AIB1 as a coactivator. This suggests a model whereby the transcriptional activity of AIB1 is squelched by a repressive mechanism utilizing the N-terminal domain and that the increased coactivator function of AIB1-Δ4 is due to the loss of this inhibitory domain. Finally, we show, using Scorpion primer technology, that AIB1-Δ4 expression is correlated with metastatic capability of human cancer cell lines.
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Chien
authors.forename: Alexander
authors.initials: A
authors.lastname: Kirilyuk
authors.forename: Jordan V
authors.initials: JV
authors.lastname: Li
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Tyler
authors.initials: T
authors.lastname: Lahusen
authors.forename: Marcel O
authors.initials: MO
authors.lastname: Schmidt
authors.forename: Annabell S
authors.initials: AS
authors.lastname: Oh
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
authors.forename: Anna T
authors.initials: AT
authors.lastname: Riegel
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016466:CHO Cells; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D000903:Antibiotics, Antineoplastic; D005231:Fatty Acids, Unsaturated; D020033:Protein Isoforms; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; C038753:leptomycin B