Identification of putative androgen receptor interaction protein modules:  Cytoskeleton and endosomes modulate AR signaling in prostate cancer cells

doi:10.1074/mcp.M600169-MCP200

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A more recent version of this article appeared on February 1, 2007. Originally published In Press as doi:10.1074/mcp.M600169-MCP200 on October 18, 2006.

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Submitted on May 8, 2006
Revised on August 31, 2006
Accepted on October 18, 2006

Identification of putative androgen receptor interaction protein modules: Cytoskeleton and endosomes modulate AR signaling in prostate cancer cells

Rohini Jasavala, Harryl D. Martinez, Jaykumar Thumar, Armann Andaya, Anne-Claude Gingras, Jimmy K. Eng, Ruedi Aebersold, David K. Han, and Michael E. Wright

Pharmacology, UC Davis, Davis, CA 95616

Corresponding Author: mewright{at}ucdavis.edu

We have developed a novel androgen receptor (AR) expression system in the 293 human embryonic kidney cell line that recapitulates AR biochemical activity as a steroid hormone receptor (SHR) in prostate cancer (PCa) cells. We used this system to identify putative AR-binding proteins in the cytosolic and nuclear compartments of mammalian cells using a large-scale co-immunoprecipitation strategy coupled to quantitative mass spectrometry. For example, the heat shock 70 and 90 chaperones, which are known regulators of SHR, were identified as AR-binding proteins. AR purification enriched for proteins involved in RNA processing, protein transport, and cytoskeletal organization, suggesting a functional link between AR and these protein modules in mammalian cells. For example, AR purification in the nuclear compartment led to the specific enrichment of $alpha$ -actinin-4, clathrin heavy chain, and serine-threonine protein kinase C $delta$ . SiRNA knockdown studies and co-transcriptional reporter assays revealed that clathrin heavy chain possessed co-activator activity during AR mediated transcription, while $alpha$ -actinin-4 and PKC $delta$ displayed both co-activator and co-repressor activity during AR-mediated transcription that was dependent upon their relative expression levels. Lastly, immunohistochemical staining of prostate tissue showed that $alpha$ -actinin-4 levels decreased in the nucleus of high grade cancerous prostate samples, suggesting its possible deregulation in advanced prostate cancers as previously observed in late-stage metastatic breast cancers. Taken together, these findings suggest AR binds to specific protein modules in mammalian cells, and that these protein modules may provide a molecular framework for interrogating AR function in normal and cancerous prostate epithelial cells.

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