Journal
JOURNAL OF CELL SCIENCE
Volume 123, Issue 8, Pages 1253-1261Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.061135
Keywords
Estrogen receptor alpha; Estrogen receptor beta; Activation domain 1; Activation domain 2; Hinge region; SRC-1; Transcriptional capacity; Tamoxifen agonism
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Funding
- Dutch Cancer Society [2005-3388, T3-107]
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Human estrogen receptors a and beta (ER alpha and ER beta) greatly differ in their target genes, transcriptional potency and cofactor-binding capacity, and are differentially expressed in various tissues. In classical estrogen response element (ERE)-mediated transactivation, ERb has a markedly reduced activation potential compared with ER alpha; the mechanism underlying this difference is unclear. Here, we report that the binding of steroid receptor coactivator-1 (SRC-1) to the AF-1 domain of ER alpha is essential but not sufficient to facilitate synergy between the AF-1 and AF-2 domains, which is required for a full agonistic response to estradiol (E2). Complete synergy is achieved through the distinct hinge domain of ER alpha, which enables combined action of the AF-1 and AF-2 domains. AF-1 of ER beta lacks the capacity to interact with SRC-1, which prevents hinge-mediated synergy between AF-1 and AF-2, thereby explaining the reduced E2-mediated transactivation of ER beta. Transactivation of ER beta by E2 requires only the AF-2 domain. A weak agonistic response to tamoxifen occurs for ER alpha, but not for ER beta, and depends on AF-1 and the hinge-region domain of ER alpha.
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