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J. Biol. Chem., Vol. 280, Issue 11, 10827-10833, March 18, 2005

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Ku Is a Novel Transcriptional Recycling Coactivator of the Androgen Receptor in Prostate Cancer Cells^*

Greg L. Mayeur, Wei-Jen Kung, Anthony Martinez, Chie Izumiya, David J. Chen, and Hsing-Jien Kung¶

From the Department of Biological Chemistry, School of Medicine, University of California, Davis, UC Davis Cancer Center, Sacramento, California 95817 and Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The androgen receptor (AR) dynamically assembles and disassembles multicomponent receptor complexes in order to respond rapidly and reversibly to fluctuations in androgen levels. We are interested in identifying the basal factors that compose the AR aporeceptor and holoreceptor complexes and impact the transcriptional process. Using tandem mass spectroscopy analysis, we identified the trimeric DNA-dependent protein kinase (DNA-PK) complex as the major AR-interacting proteins. AR directly interacts with both Ku70 and Ku80 in vivo and in vitro, as shown by co-immunoprecipitation, glutathione S-transferase pull-down, and Sf9 cell/baculovirus expression. The interaction was localized to the androgen receptor ligand binding domain and is independent of DNA interactions. Ku interacts with AR in the cytoplasm and nucleus regardless of the presence or absence of androgen. Ku acts as a coactivator of AR activity in a luciferase reporter assay employing both Ku-defective cells and Ku small interfering RNA knock-down in a prostate cancer cell line. DNA-PK catalytic subunit (DNA-PKcs) also acts as a coactivator of androgen receptor activity in a luciferase reporter assay employing DNA-PKcs defective cells. AR nuclear translocation is not affected in Ku defective cells, implying Ku functionality may be mainly nuclear. Chromatin immunoprecipitation experiments demonstrated that both Ku70 and Ku80 interact with the prostate-specific antigen promoter in an androgen-dependant manner. Finally, in vitro transcription assays demonstrated Ku involvement in transcriptional recycling with androgen dependent promoters.

Received for publication, November 27, 2004 , and in revised form, January 5, 2005.

^* This work was supported by National Institutes of Health and Department of Defense grants (to H.-J. K.) and National Institutes of Health Grants CA50519 and CA86936 (to D. J. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: UC Davis Cancer Center, Research Bldg. III, Rm. 2400B, 4645 2nd Ave., Sacramento, CA 95817. Tel.: 916-734-1538; Fax: 916-734-2589; E-mail: hkung{at}ucdavis.edu.

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