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

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...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2006-03, Vol.20 (3), p.503-515
Main Authors: Gioeli, Daniel, Black, Ben E, Gordon, Vicki, Spencer, Adam, Kesler, Cristina T, Eblen, Scott T, Paschal, Bryce M, Weber, Michael J
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Androgen Antagonists - pharmacology
Androgen Receptor Antagonists
Anilides - pharmacology
Cell Line, Tumor
Enzyme Activation
Enzyme Inhibitors - pharmacology
Humans
JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases - metabolism
Male
MAP Kinase Kinase 4 - genetics
MAP Kinase Kinase 4 - metabolism
MAP Kinase Kinase 6 - genetics
MAP Kinase Kinase 6 - metabolism
Mutation
Nitriles
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphorylation
Prostate-Specific Antigen - genetics
Prostate-Specific Antigen - metabolism
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Protein Kinases - genetics
Protein Kinases - metabolism
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Serine - metabolism
Signal Transduction
Stress, Physiological
Tosyl Compounds
Transcription, Genetic
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Summary: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 p38α 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.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2005-0351