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Cancer Genes and Genomics

DJBP: A Novel DJ-1-Binding Protein, Negatively Regulates the Androgen Receptor by Recruiting Histone Deacetylase Complex, and DJ-1 Antagonizes This Inhibition by Abrogation of This Complex^1,2

¹ Graduate School of Pharmaceutical Sciences and ² College of Medical Technology, Hokkaido University, Kita-ku, Sapporo, Japan; and
³ CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan

Requests for reprints: Hiroyoshi Ariga, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan. Phone: 81-11-706-3745; Fax: 81-11-706-4988. E-mail: hiro{at}pharm.hokudai.ac.jp

DJ-1 was identified by us as a novel oncogene that transforms mouse NIH3T3 cells in cooperation with ras. We later identified PIAS (protein inhibitor of activated STAT)x as a DJ-1-binding protein, and found that DJ-1 restored androgen receptor (AR) transcription activity that was repressed by PIASx. To further characterize the function of DJ-1, we cloned cDNA encoding a novel DJ-1-binding protein, DJBP, by a yeast two-hybrid system. DJBP mRNA was found to be specifically expressed in the testis. In addition to the binding of DJBP to the COOH-terminal region of DJ-1, DJBP was also found to bind in vitro and in vivo to the DNA-binding domain of the AR in a testosterone-dependent manner and to be colocalized with DJ-1 or AR in the nucleus. Furthermore, a co-immunoprecipitation assay showed that the formation of a ternary complex between DJ-1, DJBP, and AR occurred in cells in which DJ-1 bound to the AR via DJBP. It was found that DJBP repressed a testosterone-dependent AR transactivation activity in monkey Cos1 cells by recruiting histone deacetylase (HDAC) complex, including HDAC1 and mSin3, and that DJ-1 partially restored its repressed activity by abrogating DJBP-HDAC complex. These results suggest that AR is positively regulated by DJ-1, which antagonizes the function of negative regulators, including DJBP.

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