32 A SIGNALING NETWORKING EVOKED BY THE INTERSTITIAL CYSTITIS-ASSOCIATED FRIZZLED 8-RELATED ANTIPROLIFERATIVE FACTOR

Abstract

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research (1)1 Apr 201332 A SIGNALING NETWORKING EVOKED BY THE INTERSTITIAL CYSTITIS-ASSOCIATED FRIZZLED 8-RELATED ANTIPROLIFERATIVE FACTOR Sungyong You, Jennifer Anger, Tack Lee, Susan Keay, Michael Freeman, and Kim Jayoung Sungyong YouSungyong You Los Angeles, CA More articles by this author , Jennifer AngerJennifer Anger Los Angeles, CA More articles by this author , Tack LeeTack Lee Incheon, Korea, Republic of More articles by this author , Susan KeaySusan Keay Baltimore, MD More articles by this author , Michael FreemanMichael Freeman Los Angeles, CA More articles by this author , and Kim JayoungKim Jayoung Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1407AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Interstitial cystitis/painful bladder syndrome (IC/PBS), a chronic idiopathic visceral pain syndrome that mostly affects women, is one of the most bothersome conditions among bladder diseases. A sialoglycopeptide urinary biomarker is antiproliferative factor (APF), which has been detected in urine from approximately 95% of IC/PBS patients, is a small glycosylated peptide with 100% of homology to frizzled-8 (a receptor of Wnt signaling). A series of publications from our laboratory has previously shown that APF suppresses the proliferation rate of normal bladder epithelial cells through a mechanism that involves p53 and beta-catenin in vitro and in vivo, leading to inflammation, growth arrest, and urothelial permeability. The objectives of this study were (1) to identify the signaling networks altered in response to APF treatment in bladder epithelial cells, and (2) to understand the global network perturbed in IC/PBS in vivo by computational approaches. METHODS Chemically synthesized APF (as-APF) was used in combination with the APF-responsive hTERT-immortalized human bladder epithelial cell line, TRT-HU1. Biochemical and functional analysis including western blot, proliferation assay, immunoprecipitation and immunoflourescence staining were performed to identify the regulators of altered gene expression upon APF treatment. RESULTS Our in vitro experiments using TRT-HU1 cells showed that as-APF reduced the level of the deubiquitinase USP2a, leading to an increase in p53 expression and growth arrest. These responses to as-APF were recovered by enforced expression of USP2a, which resulted in MDM2 deubiquitination and subsequent p53 inactivation. Computational analysis of publicly available IC/PBS data sets also suggested the NF-κB pathway as an additional important regulator of IC/PBS. CONCLUSIONS Our findings suggest that as-APF functions similarly to native APF, and highlight a new mechanism by which the USP2a-MDM2-p53 signaling pathway plays an important role in the APF network. Targeting USP2a, MDM2, p53 and NF-κB may be relevant in the development of novel therapeutic approaches to block APF signaling. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e12-e13 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sungyong You Los Angeles, CA More articles by this author Jennifer Anger Los Angeles, CA More articles by this author Tack Lee Incheon, Korea, Republic of More articles by this author Susan Keay Baltimore, MD More articles by this author Michael Freeman Los Angeles, CA More articles by this author Kim Jayoung Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...