Multiple transcription factor elements collaborate with estrogen receptor alpha to activate an inducible estrogen response element in the NKG2E gene.
Estrogen receptors (ERs) regulate transcription by interacting with regulatory elements in target genes. However, known ER regulatory elements cannot explain the expression profiles of genes activated by estradiol (E2) and selective estrogen receptor modulators (SERMs). We previously showed that the killer cell lectin-like receptor (NKG2E) gene is regulated by E2, tamoxifen, and raloxifene. Here we used the NKG2E gene as a model to investigate the mechanism whereby target genes are regulated by E2 and SERMs with ERalpha. The ER regulatory element in the NKG2E promoter was mapped to the -1825 and -1686 region. Full activation of the NKG2E promoter required the collaboration between a transcription factor cluster containing c-jun, heat-shock factor 2, and CCAAT/enhancer-binding protein beta and a unique variant estrogen response element (ERE) that has only a two nucleotide spacer between half sites. The cluster elements and the variant ERE were inactive on their own, but the regulation by E2 and SERMs was restored when the c-jun, heat-shock factor-2, and CCAAT/enhancer-binding protein beta cluster was placed upstream of the variant ERE. The activation of the NKG2E gene by E2 and selective ER modulators was associated with the recruitment of the p160 coactivators glucocorticoid receptor-interacting protein 1 and amplified in breast cancer 1 but not steroid receptor coactivator 1. These studies identified one of the most complex ER regulatory units thus far reported and demonstrate that a cluster of flanking transcription factors collaborate with ER to induce a functional ERE in the NKG2E promoter.
Levy
Nitzan
N
Department of Obstetrics, Gynecology, and Reproductive Sciences, 513 Parnassus Avenue, S-1258, University of California, San Francisco, California 94143, USA.
Zhao
Xiaoyue
X
Tang
Hui
H
Jaffe
Robert B
RB
Speed
Terence P
TP
Leitman
Dale C
DC
D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D022762:CCAAT-Enhancer-Binding Proteins; D047628:Estrogen Receptor alpha; D006360:Heat-Shock Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D020845:Selective Estrogen Receptor Modulators; D014157:Transcription Factors; D013629:Tamoxifen; C070389:HSF2 protein, human; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D008156:Luciferases