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Submitted on August 30, 2005
Accepted on November 3, 2005
Department of Microbiology, Department of Biochemistry and Molecular Genetics, Center for Cell Signaling, Cancer Center, University of Virginia Health System, PO Box 800734, Charlottesville, VA 22908
* To whom correspondence should be addressed. 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 MKK4/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. siRNA-mediated knockdown of either MKK4 or MKK6 increased endogenous PSA transcript levels, and this increase was blocked by either bicalutamide or AR siRNA. Stress kinase inhibition of PSA transcription is, therefore, dependent on the AR. Similar experiments involving either activation or inhibition of MEK/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.
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