Coactivator selective regulation of androgen receptor activity.
The androgen receptor (AR) is a ligand activated nuclear receptor, which regulates transcription and stimulates growth of androgen dependent prostate cancer. To regulate transcription, AR recruits a series of coactivators that modify chromatin and facilitate transcription. However, information on ligand and target gene-specific requirements for coactivators is limited. We compared the actions of the p160 coactivators SRC-1 and SRC-3/RAC3 with SRA (steroid receptor RNA activator). All three coactivate AR in the presence of agonist as expected. However, overexpression of either SRC-1 or SRC-3 increased AR activity in response to the partial antagonist, cyproterone acetate, whereas SRA was unable to stimulate AR activity under these conditions. Using siRNA to reduce expression of these coactivators in LNCaP cells, we also found promoter specific requirement for these coactivators. SRC-3 is required for optimal androgen dependent induction of PSA, TMPRSS2, and PMEPA1 whereas SRA is required only for optimal induction of the TMPRSS2 gene. These data indicate that different groups of AR target genes have distinct requirements for coactivators and response to AR ligands.
Agoulnik
Irina U
IU
Department of Molecular and Cellular Biology, Baylor College of Medicine, M130, One Baylor Plaza, Houston, TX 77030, United States.
Weigel
Nancy L
NL
D000728:Androgens; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017373:Cyproterone Acetate / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D011471:Prostatic Neoplasms / Q000473:pathology; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D000728:Androgens; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D011944:Receptors, Androgen; D014157:Transcription Factors; C405423:steroid receptor RNA activator; D017373:Cyproterone Acetate; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3