Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells.
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.
Baek
Sung Hee
SH
Department of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, South Korea. sbaek@snu.ac.kr
Ohgi
Kenneth A
KA
Nelson
Charles A
CA
Welsbie
Derek
D
Chen
Charlie
C
Sawyers
Charles L
CL
Rose
David W
DW
Rosenfeld
Michael G
MG
D000494:Allosteric Regulation; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008024:Ligands; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
D059002:Androgen Receptor Antagonists; D000728:Androgens; D007375:Interleukin-1; D008024:Ligands; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D050880:p300-CBP Transcription Factors