Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription.
Many cofactors bind the hormone-activated estrogen receptor (ER), yet the specific regulators of endogenous ER-mediated gene transcription are unknown. Using chromatin immunoprecipitation (ChIP), we find that ER and a number of coactivators rapidly associate with estrogen responsive promoters following estrogen treatment in a cyclic fashion that is not predicted by current models of hormone activation. Cycles of ER complex assembly are followed by transcription. In contrast, the anti-estrogen tamoxifen (TAM) recruits corepressors but not coactivators. Using a genetic approach, we show that recruitment of the p160 class of coactivators is sufficient for gene activation and for the growth stimulatory actions of estrogen in breast cancer supporting a model in which ER cofactors play unique roles in estrogen signaling.
Shang
Y
Y
Department of Adult Oncology Dana-Farber Cancer Institute and Harvard Medical School 02115, Boston, MA, USA.
Hu
X
X
DiRenzo
J
J
Lazar
M A
MA
Brown
M
M
D001943:Breast Neoplasms; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006657:Histones / Q000737:chemistry; D006801:Humans; D046911:Macromolecular Substances; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D002843:Chromatin; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D006657:Histones; D046911:Macromolecular Substances; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D011506:Proteins; D011960:Receptors, Estrogen; C051838:TFF1 protein, human; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D004958:Estradiol; D056921:Nuclear Receptor Coactivator 3; D002402:Cathepsin D