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Molecular & Cellular Proteomics 6:252-271, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Identification of Putative Androgen Receptor Interaction Protein Modules

Cytoskeleton and Endosomes Modulate Androgen Receptor Signaling in Prostate Cancer Cells^*,S

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

From the University of California Davis Genome Center, Department of Pharmacology, UC Davis School of Medicine, Davis, California 95616, Department of Cell Biology, Center for Vascular Biology, University of Connecticut School of Medicine, Farmington, Connecticut 06269, ^¶ Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada, ^|| Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, ^** Institute of Molecular Systems Biology, ETH Zurich and Faculty of Sciences, University of Zurich, 8092 Zurich, Switzerland, and Institute for Systems Biology, Seattle, Washington 98103

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 in prostate cancer 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 steroid hormone receptor, 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 -actinin-4, clathrin heavy chain, and serine-threonine protein kinase C . Short interfering RNA knockdown studies and co-transcriptional reporter assays revealed that clathrin heavy chain possessed co-activator activity during AR-mediated transcription, whereas -actinin-4 and protein kinase C 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 -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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