A Synthetic Form of Frizzled 8-Associated Antiproliferative Factor Enhances p53 Stability through USP2a and MDM2

被引：9

作者：

Kim, Jayoung ^{[1
,2
,3
,4
,5
]}

Keay, Susan K. ^{[6
,7
]}

You, Sungyong ^{[1
,2
]}

Loda, Massimo ^{[8
,9
,10
]}

Freeman, Michael R. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Surg, Div Canc Biol & Therapeut, Los Angeles, CA 90048 USA

[2] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Biomed Sci, Los Angeles, CA 90048 USA

[3] Childrens Hosp, Urol Dis Res Ctr, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[6] Univ Maryland, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21201 USA

[7] VA Maryland Hlth Care Ctr, Baltimore, MD USA

[8] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA USA

[9] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA

来源：

PLOS ONE | 2012年 / 7卷 / 12期

关键词：

EPIDERMAL-GROWTH-FACTOR; BLADDER EPITHELIAL-CELLS; INTERSTITIAL-CYSTITIS; TUMOR-SUPPRESSOR; URINE MARKERS; CYCLIN D1; PATHWAY; EXPRESSION; PROLIFERATION; CKAP4/P63;

D O I：

10.1371/journal.pone.0050392

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Frizzled 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. Citation: Kim J, Keay SK, You S, Loda M, Freeman MR (2012) A Synthetic Form of Frizzled 8-Associated Antiproliferative Factor Enhances p53 Stability through USP2a and MDM2. PLoS ONE 7(12): e50392. doi:10.1371/journal.pone.0050392

引用

页数：11

共 54 条

[1] MdmX is a substrate for the deubiquitinating enzyme USP2a [J].