title: Androgen Receptor Splice Variants Dimerize to Transactivate Target Genes.
abstract: Constitutively active androgen receptor splice variants (AR-V) lacking the ligand-binding domain have been implicated in the pathogenesis of castration-resistant prostate cancer and in mediating resistance to newer drugs that target the androgen axis. AR-V regulates expression of both canonical AR targets and a unique set of cancer-specific targets that are enriched for cell-cycle functions. However, little is known about how AR-V controls gene expression. Here, we report that two major AR-Vs, termed AR-V7 and AR(v567es), not only homodimerize and heterodimerize with each other but also heterodimerize with full-length androgen receptor (AR-FL) in an androgen-independent manner. We found that heterodimerization of AR-V and AR-FL was mediated by N- and C-terminal interactions and by the DNA-binding domain of each molecule, whereas AR-V homodimerization was mediated only by DNA-binding domain interactions. Notably, AR-V dimerization was required to transactivate target genes and to confer castration-resistant cell growth. Our results clarify the mechanism by which AR-Vs mediate gene regulation and provide a pivotal pathway for rational drug design to disrupt AR-V signaling as a rational strategy for the effective treatment of advanced prostate cancer.
authors.affiliation: College of Life Sciences, Jilin University, Changchun, China. Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana. School of Nursing, Jilin University, Changchun, China.
authors.forename: Duo
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Qi
authors.affiliation: College of Life Sciences, Jilin University, Changchun, China. Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
authors.forename: Bo
authors.initials: B
authors.lastname: Cao
authors.affiliation: College of Life Sciences, Jilin University, Changchun, China. Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Bai
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Bio-X Program and Department of Radiology, Stanford University School of Medicine, Stanford, California.
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
authors.affiliation: Department of Urology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana. Department of Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
authors.forename: Erik K
authors.initials: EK
authors.lastname: Flemington
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana.
authors.forename: Chang-Deng
authors.initials: CD
authors.lastname: Hu
authors.affiliation: College of Life Sciences, Jilin University, Changchun, China. Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana. National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China. ydong@tulane.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000728:Androgens / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D006801:Humans; D008024:Ligands; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000728:Androgens; D004268:DNA-Binding Proteins; D008024:Ligands; D020033:Protein Isoforms; D011944:Receptors, Androgen