This Article Full Text Full Text (PDF) Supplemental Data Files All Versions of this Article: 20/3/503    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gioeli, D. Articles by Weber, M. J. Search for Related Content PubMed PubMed Citation Articles by Gioeli, D. Articles by Weber, M. J.

Stress Kinase Signaling Regulates Androgen Receptor Phosphorylation, Transcription, and Localization

Department of Microbiology (D.G., V.G., C.T.K., S.T.E., M.J.W.), Department of Biochemistry and Molecular Genetics (B.E.B., A.S., C.T.K., B.M.P.), Center for Cell Signaling (B.E.B., A.S., C.T.K., B.M.P.), Cancer Center (D.G., V.G., C.T.K., S.T.E., B.M.P., M.J.W.), University of Virginia Health System, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Daniel Gioeli, Department of Microbiology, P.O. Box 800734, University of Virginia Health System, Charlottesville, Virginia 22908. E-mail: dgg3f{at}virginia.edu.

Activation of signal transduction kinase cascades is known to alter androgen receptor (AR) activity, but the molecular mechanisms are still poorly defined. Here we show that stress kinase signaling regulates Ser 650 phosphorylation and AR nuclear export. In LNCaP prostate cancer cells, activation of either MAPK kinase (MKK) 4:c-Jun N-terminal kinase (JNK) or MKK6:p38 signaling pathways increased Ser 650 phosphorylation, whereas pharmacologic inhibition of JNK or p38 signaling led to a reduction of AR Ser 650 phosphorylation. Both p38 and JNK1 phosphorylated Ser 650 in vitro. Small interfering RNA-mediated knockdown of either MKK4 or MKK6 increased endogenous prostate-specific antigen (PSA) transcript levels, and this increase was blocked by either bicalutamide or AR small interfering RNA. Stress kinase inhibition of PSA transcription is, therefore, dependent on the AR. Similar experiments involving either activation or inhibition of MAPK/ERK kinase:ERK signaling had little effect on Ser 650 phosphorylation or PSA mRNA levels. Ser 650 is proximal to the DNA binding domain that contains a nuclear export signal. Mutation of Ser 650 to alanine reduced nuclear export of the AR, whereas mutation of Ser 650 to the phosphomimetic amino acid aspartate restored AR nuclear export. Pharmacologic inhibition of stress kinase signaling reduced wild-type AR nuclear export equivalent to the S650A mutant without affecting nuclear export of the S650D mutant. Our data suggest that stress kinase signaling and nuclear export regulate AR transcriptional activity.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Ligands:   Dihydrotestosterone  |  R1881

This article has been cited by other articles:

				L. C. Shank, J. B. Kelley, D. Gioeli, C.-S. Yang, A. Spencer, L. A. Allison, and B. M. Paschal Activation of the DNA-dependent Protein Kinase Stimulates Nuclear Export of the Androgen Receptor in Vitro J. Biol. Chem., April 18, 2008; 283(16): 10568 - 10580. [Abstract] [Full Text] [PDF]

				H. Zong, Y. Chi, Y. Wang, Y. Yang, L. Zhang, H. Chen, J. Jiang, Z. Li, Y. Hong, H. Wang, et al. Cyclin D3/CDK11p58 Complex Is Involved in the Repression of Androgen Receptor Mol. Cell. Biol., October 15, 2007; 27(20): 7125 - 7142. [Abstract] [Full Text] [PDF]

				G. Buchanan, C. Ricciardelli, J. M. Harris, J. Prescott, Z. C.-L. Yu, L. Jia, L. M. Butler, V. R. Marshall, H. I. Scher, W. L. Gerald, et al. Control of Androgen Receptor Signaling in Prostate Cancer by the Cochaperone Small Glutamine Rich Tetratricopeptide Repeat Containing Protein {alpha} Cancer Res., October 15, 2007; 67(20): 10087 - 10096. [Abstract] [Full Text] [PDF]

				N. L. Weigel and N. L. Moore Steroid Receptor Phosphorylation: A Key Modulator of Multiple Receptor Functions Mol. Endocrinol., October 1, 2007; 21(10): 2311 - 2319. [Abstract] [Full Text] [PDF]

				C. T. Kesler, D. Gioeli, M. R. Conaway, M. J. Weber, and B. M. Paschal Subcellular Localization Modulates Activation Function 1 Domain Phosphorylation in the Androgen Receptor Mol. Endocrinol., September 1, 2007; 21(9): 2071 - 2084. [Abstract] [Full Text] [PDF]

				I. Palazzolo, B. G. Burnett, J. E. Young, P. L. Brenne, A. R. La Spada, K. H. Fischbeck, B. W. Howell, and M. Pennuto Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity Hum. Mol. Genet., July 1, 2007; 16(13): 1593 - 1603. [Abstract] [Full Text] [PDF]

				C.-S. Yang, H.-W. Xin, J. B. Kelley, A. Spencer, D. L. Brautigan, and B. M. Paschal Ligand Binding to the Androgen Receptor Induces Conformational Changes That Regulate Phosphatase Interactions Mol. Cell. Biol., May 1, 2007; 27(9): 3390 - 3404. [Abstract] [Full Text] [PDF]

				A. G. Papatsoris, M. V. Karamouzis, and A. G. Papavassiliou The power and promise of "rewiring" the mitogen-activated protein kinase network in prostate cancer therapeutics Mol. Cancer Ther., March 1, 2007; 6(3): 811 - 819. [Abstract] [Full Text] [PDF]

				M. A. Bogoyevitch and B. Kobe Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases Microbiol. Mol. Biol. Rev., December 1, 2006; 70(4): 1061 - 1095. [Abstract] [Full Text] [PDF]

				S. Kraus, D. Gioeli, T. Vomastek, V. Gordon, and M. J. Weber Receptor for Activated C Kinase 1 (RACK1) and Src Regulate the Tyrosine Phosphorylation and Function of the Androgen Receptor. Cancer Res., November 15, 2006; 66(22): 11047 - 11054. [Abstract] [Full Text] [PDF]