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Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3100-5. Epub 2006 Feb 21.

Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells.

Author information

1
Department of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, South Korea. sbaek@snu.ac.kr

Abstract

The androgen receptor not only mediates prostate development but also serves as a key regulator of primary prostatic cancer growth. Although initially responsive to selective androgen receptor modulators (SARMs), which cause recruitment of the nuclear receptor-corepressor (N-CoR) complex, resistance invariably occurs, perhaps in response to inflammatory signals. Here we report that dismissal of nuclear receptor-corepressor complexes by specific signals or androgen receptor overexpression results in recruitment of many of the cohorts of coactivator complexes that permits SARMs and natural ligands to function as agonists. SARM-bound androgen receptors appear to exhibit failure to recruit specific components of the coactivators generally bound by liganded nuclear receptors, including cAMP response element-binding protein (CBP)/p300 or coactivator-associated arginine methyltransferase 1 (CARM1) to the SARM-bound androgen receptor, although still causing transcriptional activation of androgen receptor target genes. SARM-bound androgen receptors use distinct LXXLL (L, leucine; X, any amino acid) helices in the p160 nuclear receptor interaction domains that may impose selective allosteric effects, providing a component of the molecular basis of differential responses to different classes of ligands by androgen receptor.

PMID:
16492776
PMCID:
PMC1413901
DOI:
10.1073/pnas.0510842103
[Indexed for MEDLINE]
Free PMC Article
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