Mueller Stefan O, Katzenellenbogen John A, Korach Kenneth S
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Steroids. 2004 Sep;69(10):681-6. doi: 10.1016/j.steroids.2004.06.004.
The estrogen receptor (ER) alpha is a hormone-inducible transcription factor that has a pivotal physiological role. Intriguingly, a clear and undisputed physiological function of the recently described ERbeta remains elusive, with the exception of the ovary where a cooperative role of ERalpha and ERbeta has been demonstrated. We have, therefore, investigated whether endogenous ERs, in particular ERbeta, act as ligand-inducible transcription factors in primary ovarian cells derived from wild-type, ERalpha or ERbeta knockout mice. Granulosa-enriched cell fractions naturally expressing ERbeta and thecal cell fractions that express ERalpha were analyzed in transactivation assays using the vitellogenin A2 consensus estrogen response element and potent ER agonists diethylstilbestrol and S-indenestrol A. We studied also the potency-selective ERbeta agonist R-indenestrol A, the pure ERalpha agonist and ERbeta antagonist R,R-diethyl-tetrahydrochrysene and the pure ERalpha agonist propylpyrazole-triol. Using ER subtype-specific physiological cell models and these ER subtype-specific structural probes, we analyzed trans-activation of ERalpha and ERbeta. This analysis revealed that endogenously expressed ERbeta is indeed functional as a transcription factor, that it responds to estrogens appropriately, and that the ligands used are true ER subtype-specific probes in primary ovarian cells. In conclusion, this study demonstrates that endogenously expressed ERbeta is capable of regulating gene transcription independent of ERalpha.
雌激素受体（ER）α是一种激素诱导型转录因子，具有关键的生理作用。有趣的是，除了在卵巢中已证明ERα和ERβ具有协同作用外，最近描述的ERβ的明确且无可争议的生理功能仍然难以捉摸。因此，我们研究了内源性ER，特别是ERβ，在源自野生型、ERα或ERβ基因敲除小鼠的原代卵巢细胞中是否作为配体诱导型转录因子发挥作用。在反式激活试验中，使用卵黄蛋白原A2共有雌激素反应元件以及强效ER激动剂己烯雌酚和S-茚地那酯A，对天然表达ERβ的富含颗粒细胞的组分和表达ERα的卵泡膜细胞组分进行了分析。我们还研究了效价选择性ERβ激动剂R-茚地那酯A、纯ERα激动剂和ERβ拮抗剂R,R-二乙基-四氢 Chrysene以及纯ERα激动剂丙基吡唑三醇。使用ER亚型特异性生理细胞模型和这些ER亚型特异性结构探针，我们分析了ERα和ERβ的反式激活。该分析表明，内源性表达的ERβ确实作为转录因子发挥功能，它对雌激素有适当反应，并且所使用的配体在原代卵巢细胞中是真正的ER亚型特异性探针。总之，本研究表明内源性表达的ERβ能够独立于ERα调节基因转录。
