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J. Biol. Chem., Vol. 283, Issue 16, 10568-10580, April 18, 2008

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Activation of the DNA-dependent Protein Kinase Stimulates Nuclear Export of the Androgen Receptor in Vitro^*

Leonard C. Shank, Joshua B. Kelley, Daniel Gioeli^¶, Chun-Song Yang, Adam Spencer, Lizabeth A. Allison^||, and Bryce M. Paschal^¶1

From the Center for Cell Signaling, Department of Biochemistry and Molecular Genetics, and ^¶Cancer Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 and the ^||Department of Biology, the College of William and Mary, Williamsburg, Virginia 23187

The androgen receptor undergoes nuclear import in response to ligand, but the mechanism by which it undergoes nuclear export is poorly understood. We developed a permeabilized cell assay to characterize nuclear export of the androgen receptor in LNCaP prostate cancer cells. We found that nuclear export of endogenous androgen receptor can be stimulated by short double-stranded DNA oligonucleotides. This androgen receptor export pathway is dependent on ATP hydrolysis and is enhanced by phosphatase inhibition with okadaic acid. Fluorescence recovery after photobleaching in permeabilized cells, under the conditions that stimulate androgen receptor export, suggested that double-stranded DNA-dependent export does not simply reflect the relief of a nuclear retention mechanism. A radiolabeled androgen was used to show that the androgen receptor remains ligand-bound during translocation through the nuclear pore complex. A specific inhibitor to the DNA-dependent protein kinase, NU7026, inhibits androgen receptor export and phosphorylation. In living cells, NU7026 treatment increases androgen-dependent transcription from endogenous genes that are regulated by androgen receptor. We suggest that DNA-dependent protein kinase phosphorylation of the androgen receptor, or an interacting component, helps target the androgen receptor for export from the nucleus.

Received for publication, January 30, 2008

^* 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.

¹ To whom correspondence should be addressed: Center for Cell Signaling, Dept. of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Box 800577, Charlottesville, VA 22908. Tel.: 434-243-6521; Fax: 434-924-1236; E-mail: paschal{at}virginia.edu.

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