title: Poly (A) Binding Protein Cytoplasmic 1 Is a Novel Co-Regulator of the Androgen Receptor.
abstract: The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene expression in a ligand-dependent manner. The NTD of the AR plays a key role in AR transactivation including androgen-independent activation of the AR in castration-resistant prostate cancer (CRPC) cells. We recently reported that amino acids (a.a.) 50-250 of the NTD are capable of modulating AR nucleocytoplasmic trafficking. To further explore the mechanism associated with a.a. 50-250, GFP pull-down assays were performed in C4-2 CRPC cells transfected with GFP tagged a.a. 50-250 of the AR. Mass spectrometry analysis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR. In silico analysis of gene expression data revealed PABPC1 up-regulation in prostate cancer tissue specimens and this up-regulation correlates to increased disease recurrence. Co-immunoprecipitation assays confirmed the association of PABPC1 with a.a. 50-250 of the NTD of the AR. Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells. Additionally, knockdown of PABPC1 inhibited transactivation of the PSA promoter by NAR (AR lacking the LBD) and attenuated proliferation of AR-positive prostate cancer cells. These findings suggest that PABPC1 is a novel co-regulator of the AR and may be a potential target for blocking activation of the AR in CRPC.
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Kurtis
authors.initials: K
authors.lastname: Eisermann
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; Central Laboratory College of Science, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Javid A
authors.initials: JA
authors.lastname: Dar
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; Division of Biotechnology, Sher-e-Kashmir University of Agricultural Sciences and Technology, Shalimar, Srinagar, J&K, India.
authors.forename: Khalid Z
authors.initials: KZ
authors.lastname: Masoodi
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D039122:Poly(A)-Binding Protein I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D040901:Proteomics; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D012008:Recurrence; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D039122:Poly(A)-Binding Protein I; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen