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Original Paper

Free Access

Transcriptional Regulation of RKIP Expression by Androgen in Prostate Cells

Zhang H.a · Wu J.b · Keller J.M.a · Yeung K.c · Keller E.T.a · Fu Z.b

Author affiliations

aUniversity of Michigan Comprehensive Cancer Center and Department of Urology, University of Michigan Health System, Ann Arbor, MI; bDepartment of Human and Molecular Genetics, VCU Institute of Molecular Medicine and VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA; cDepartment of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, OH

Corresponding Author

Zheng Fu and Evan T. Keller

Department of Human and Molecular Genetics, Virginia Commonwealth University

Richmond, VA 23298 (USA) and Department of Urology, University of Michigan Medical

School, 5304 CCC, 1500 E. Medical Center Dr. Ann Arbor, MI 48109-0940 (USA)

E-Mail zfu@vcu.edu and E-Mail etkeller@umich.edu

Related Articles for ""

Cell Physiol Biochem 2012;30:1340-1350

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Background/Aims: Raf kinase inhibitory protein (RKIP) is a scaffolding molecule in the PEBP family that sequesters certain signaling molecules away from their pathways, thereby abrogating intracellular growth signals. RKIP has been assigned multiple functions and is associated with an increasing number of diseases through its involvement with signal transduction pathways. We previously demonstrated that RKIP is highly expressed in human normal prostate epithelial cells and plays a pivotal role during prostate cancer (PCa) progression. Whether RKIP is subject to endocrine regulation has not been reported. Methods: The effect of dihydrotestosterone (DHT) on RKIP expression in normal prostate epithelial cells was determined by real-time RT-PCR and Western blot. Report assay was performed to determine whether the regulation of RKIP by androgens is at the transcriptional level. The binding of androgen receptor (AR) to the RKIP promoter was determined by EMSA and Chromatin Immunoprecipitation (ChIP) assays. To determine whether RKIP was regulated by androgen in vivo, we examined RKIP expression level in response to castration in 6-8 week old C57BL/6 male mice. Results: Here we report that DHT positively regulates the transcription of RKIP in the normal prostate epithelial cells. The anti-androgen bicalutamide blocked androgen-mediated regulation of RKIP, which indicates that this regulation is mediated through AR. Transfection of the cells with a RKIP promoter-driven luciferase reporter vector showed that DHT increased RKIP promoter activity in parallel with changes in expression. EMSA demonstrates that AR binds to a putative ARE in the RKIP promoter, which was further validated by ChIP assay. Importantly, these data are further supported by our in vivo experiment where castrated mice had less RKIP expression in their prostate glands than sham-operated mice. Conclusions: Collectively, the results establish RKIP as a novel androgen target gene. Androgens induce RKIP expression through AR-mediated transcriptional modulation of the RKIP promoter in the prostate. This is the first demonstration of endocrine regulation of the metastasis suppressor gene RKIP.

© 2012 S. Karger AG, Basel

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: September 27, 2012
Published online: October 23, 2012
Issue release date: December 2012

Number of Print Pages: 11
Number of Figures: 0
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: http://www.karger.com/CPB

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