Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids
Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids
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DOI：
10.1172/jci200317261
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发表时间：
2003-06-01
影响因子：
15.9
通讯作者：
Manolagas, SC
中科院分区：
文献类型：
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作者：
Kousteni, S;Han, L;Manolagas, SC
已经发现，4-雌激素-3 α，17 β-二醇，一种不影响经典转录的雌激素受体（ER）或雄激素受体（AR）的合成配体，逆转了切除卵巢的女性或切除卵巢的男性的骨丢失，而不影响子宫或精囊，证明性类固醇受体的经典遗传向性作用是其骨保护作用的结果，但它们对生殖器官的影响不可或缺。我们现在已经研究了这种化合物的作用机理。我们报道，与17 β-雌二醇或双氢睾酮相同，但与雷洛昔芬不同，雌激素通过ER或AR的促核作用改变Elk-1、CCAAT增强子结合蛋白-β（C/EBP β）和环腺苷酸反应元件结合蛋白（CREB）或c-Jun/c-Fos的活性，分别导致Src/Shc/ERK通路的激活或JNK的下调。所有这些作用都是非性别特异性的，只需要受体的配体结合结构域，并且对于这些配体对成骨细胞和HeLa细胞的抗凋亡作用是必不可少的。此外，给卵巢切除小鼠施用17 β-雌二醇或4-雌甾-3 α，17 β-二醇诱导ERK、Elk-1和C/EBP β的磷酸化，下调c-Jun，并上调ERK/SRE靶基因EBP-1的表达。激酶启动的常用转录因子的调节提供了一个深刻的性类固醇受体配体，包括合成的，是缺乏经典的转录活性的骨骼效应的分子解释。
It has been found that 4-estren-3alpha,17beta-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17beta-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-beta (C/EBPbeta), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligand-binding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17beta-estradiol or 4-estren-3a,17p-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPbeta, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.