Estrogen receptor β isoform-specific induction of transforming growth factor β-inducible early gene-1 in human osteoblast cells:: An essential role for the activation function 1 domain
Estrogen receptor β isoform-specific induction of transforming growth factor β-inducible early gene-1 in human osteoblast cells:: An essential role for the activation function 1 domain
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DOI：
10.1210/me.2007-0253
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发表时间：
2008-07-01
影响因子：
--
通讯作者：
Spelsberg, Thomas C.
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文献类型：
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作者：
Hawse, John R.;Subramaniam, Malayannan;Spelsberg, Thomas C.
雌激素受体(ER) α和β是重要的配体介导的转录因子，已知在包括骨在内的许多组织中发挥重要的生物学作用。尽管这些受体具有高度的同源性，但最近的研究表明，它们的功能在很大程度上是独特的。尽管这些受体已经被详细研究了十多年，但关于这两种蛋白质调节不同基因的机制的数据很少。以TGF β诱导的早期基因-1 （TIEG）为模型，我们证明了在成骨细胞中，TIEG可以被ER β而不是ER α快速诱导以响应雌激素。我们已经确定了ER β利用的调控元件，并证明ER β将类固醇受体共激活因子（SRC） 1和SRC2招募到该调控区域。此外，ER β活化功能1 （AF1）结构域的缺失显著降低了TIEG的雌激素诱导。通过使用嵌合受体，我们已经证明ER β的AF1结构域负责募集SRC1和SRC2并诱导成骨细胞中TIEG的表达。最后，SRC1，而不是SRC2，是ER β诱导TIEG所必需的。总的来说，这些数据表明雌激素诱导TIEG是ER β特异性的，ER β的AF1结构域赋予了这种特异性。最后，内质网β的AF1在特异性共激活因子的募集中发挥了一个新的重要作用，这表明AF1可能在这两种受体对基因表达的调节差异中发挥了重要作用。
The estrogen receptors (ER) alpha and beta are important ligand-mediated transcription factors known to play significant biological roles in numerous tissues including bone. Despite the high homology shared by these receptors, recent studies have suggested that their function is largely unique. Although these receptors have been studied in detail for more than a decade, little data exist concerning the mechanisms by which these two proteins regulate distinct sets of genes. Using the TGF beta-inducible early gene-1 (TIEG) as a model, we demonstrate that TIEG is rapidly induced in response to estrogen in osteoblasts by ER beta, but not ER alpha. We have identified the regulatory elements utilized by ER beta and have demonstrated that ER beta recruits steroid receptor coactivator (SRC) 1 and SRC2 to this regulatory region. Additionally, deletion of the ER beta-activation function 1 (AF1) domain drastically decreases the estrogen induction of TIEG. Through the use of chimeric receptors, we have demonstrated that the AF1 domain of ER beta is responsible for recruiting SRC1 and SRC2 and inducing the expression of TIEG in osteoblasts. Finally, SRC1, but not SRC2, is essential for TIEG induction by ER beta. Overall, these data demonstrate that the estrogen induction of TIEG is ER beta specific and that the AF1 domain of ER beta confers this specificity. Finally, a novel and important role for ER beta's AF1 is implicated in the recruitment of specific coactivators, suggesting that the AF1 may play a significant role in conferring the differences in regulation of gene expression by these two receptors.