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dc.contributor.authorKim, Jayoung
dc.contributor.authorKeay, Susan K.
dc.contributor.authorYou, Sungyong
dc.contributor.authorLoda, Massimo
dc.contributor.authorFreeman, Michael R.
dc.date.accessioned2013-04-24T20:45:04Z
dc.date.issued2012
dc.identifier.citationKim, Jayoung, Susan K. Keay, Sungyong You, Massimo Loda, and Michael R. Freeman. 2012. A synthetic form of frizzled 8-associated antiproliferative factor enhances p53 stability through USP2a and MDM2. PLoS ONE 7(12): e50392.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10582117
dc.description.abstractFrizzled 8-associated Antiproliferative Factor (APF) is a sialoglycopeptide urinary biomarker of interstitial cystitis/painful bladder syndrome (IC/PBS), a chronic condition of unknown etiology with variable symptoms that generally include pelvic and/or perineal pain, urinary frequency, and urgency. We previously reported that native human APF suppresses the proliferation of normal bladder epithelial cells through a mechanism that involves increased levels of p53. The goal of this study was to delineate the regulatory mechanism whereby p53 expression is regulated by APF. Two APF-responsive cell lines (T24 bladder carcinoma cells and the immortalized human bladder epithelial cell line, TRT-HU1) were treated with asialo-APF (as-APF), a chemically synthesized form of APF. Biochemical analysis revealed that as-APF increased p53 levels in two ways: by decreasing ubiquitin specific protease 2a (USP2a) expression leading to enhanced ubiquitination of murine double minute 2 E3 ubiquitin ligase (MDM2), and by suppressing association of p53 with MDM2, thus impairing p53 ubiquitination. Biological responses to as-APF were suppressed by increased expression of wild type, but not mutant USP2a, which enhanced cell growth via upregulation of a cell cycle mediator, cyclin D1, at both transcription and protein levels. Consistent with this, gene silencing of USP2a with siRNA arrested cell proliferation. Our findings suggest that APF upregulates cellular p53 levels via functional attenuation of the USP2a-MDM2 pathway, resulting in p53 accumulation and growth arrest. These data also imply that targeting USP2a, MDM2, p53 and/or complex formation by these molecules may be relevant in the development of novel therapeutic approaches to IC/PBS.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0050392en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516501/pdf/en_US
dash.licenseLAA
dc.subjectBiologyen_US
dc.subjectBiochemistryen_US
dc.subjectProteinsen_US
dc.subjectProtein Interactionsen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectSignal Transductionen_US
dc.subjectCrosstalken_US
dc.subjectCell Growthen_US
dc.subjectProteomicsen_US
dc.subjectMedicineen_US
dc.subjectUrologyen_US
dc.subjectFemale Urologyen_US
dc.subjectUrodynamicsen_US
dc.subjectSignal Transduction Mechanismsen_US
dc.subjectBladder Disordersen_US
dc.subjectUreteric Disordersen_US
dc.titleA Synthetic Form of Frizzled 8-Associated Antiproliferative Factor Enhances p53 Stability through USP2a and MDM2en_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorFreeman, Michael R.
dc.date.available2013-04-24T20:45:04Z
dc.identifier.doi10.1371/journal.pone.0050392*
dash.contributor.affiliatedKim, Jayoung
dash.contributor.affiliatedFreeman, Michael R.
dash.contributor.affiliatedLoda, Massimo


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