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Multiple Transcription Factor Elements Collaborate with Estrogen Receptor to Activate an Inducible Estrogen Response Element in the NKG2E Gene

Departments of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Sciences (N.L., R.B.J., D.C.L), and Cellular and Molecular Pharmacology (N.L., D.C.L), University of California, San Francisco, California 94143; Department of Statistics (X.Z, H.T., T.P.S.), University of California, Berkeley, California 94720; and Division of Genetics and Bioinformatics (T.P.S.), The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia

Address all correspondence and requests for reprints to: Dale Leitman, Department of Obstetrics, Gynecology, and Reproductive Sciences, 513 Parnassus Avenue, S-1258, San Francisco, California 94143. E-mail: leitmand{at}obgyn.ucsf.edu.

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 ER. 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 ß 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 ß 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.