Journal
ENDOCRINOLOGY
Volume 150, Issue 6, Pages 2674-2682Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2008-1181
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Funding
- Prostate Cancer Foundation of Australia [YI02]
- The National Health and Medical Research Council of Australia [453662]
- U.S. Department of Defense [PC060443]
- National Institutes of Health [P50 CA92629]
- Memorial Sloan Kettering Cancer Center Special Program in Research Excellence in prostate cancer
- PepsiCo Foundation
- Prostate Cancer Foundation
- National Health Medical Research Council C. J. Martin Biomedical Fellowship
- Freemasons Foundation postdoctoral fellowship
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The androgen receptor (AR) is an important signaling molecule in multiple tissues, yet its mode of action and cell-specific activities remain enigmatic. AR function has been best studied in the prostate, in which it is essential for growth and homeostasis of the normal organ as well as each stage of cancer development. Investigation of mechanisms responsible for continued AR action that evolve during prostate cancer progression or after hormonal management of the disease have been instructive in defining AR signaling pathways. In the current paper, we use sequence similarity and the collocation of somatic mutations in prostate cancer to define residues 501-535 of the AR amino-terminal domain as an important mediator of receptor function. Specifically, the 501-535 region is required for optimal interaction of the amino-terminal domain with both the p160 coactivator, nuclear receptor coactivator-2, and the AR-ligand binding domain in the amino/carboxyl (N/C) interaction. The N/C interaction is decreased by deletion of the 501-535 region but is distinct from deletion of the (23)FQNLF(27) peptide in that it does not affect the capacity of the AR to activate transcription from a chromatin integrated reporter or recruitment of the receptor to androgen-responsive loci in vivo. Collectively, we have been able to outline two classes of N/C-deficient AR variant that are divergent in their capacity to act in a chromatin context, thereby further defining the interplay between N/C interaction and coregulator recruitment via multiple receptor domains. These mechanisms are likely to be key determinants of the cell and promoter specific activities of the AR. (Endocrinology 150: 2674-2682, 2009)
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