The role of CBP in estrogen receptor cross-talk with nuclear factor-κB in HepG2 cells
The role of CBP in estrogen receptor cross-talk with nuclear factor-κB in HepG2 cells
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DOI：
10.1210/en.141.9.3403
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发表时间：
2000-09-01
期刊：
影响因子：
4.8
通讯作者：
Karathanasis, SK
中科院分区：
文献类型：
--
作者：
Harnish, DC;Scicchitano, MS;Karathanasis, SK
配体激活的核受体与促炎转录因子核因子-κ B（NF-κ B）之间的功能相互作用或串扰可能在配体介导的疾病过程的修饰中起主要作用。特别是，雌激素替代疗法的心脏保护作用被认为部分是由于配体结合的雌激素受体（ER）抑制NF-κ B功能的能力。在目前的研究中，17 β-雌二醇结合的ER α干扰了HepG 2细胞中马槟榔诱导的NF-κ B报告基因的激活。雌激素代谢物17 α-乙炔雌二醇和植物雌激素染料木黄酮也是NF-κ B激活的有效抑制剂，而他莫昔芬、4-羟基他莫昔芬和雷洛昔芬则无活性。这种抑制是相互的，因为NF-κ B干扰ER α的反式激活特性。配体结合的ER α不抑制NF-κ B与DNA的结合，但它确实降低了NF-κ B转录活性所需的组蛋白乙酰转移酶活性。共表达转录辅激活因子CREB结合蛋白（CBP），而不是类固醇受体辅激活因子1a，逆转了ER α介导的NF-κ B活性抑制。哺乳动物双杂交实验也揭示了配体结合的ER α可以与CBP-NF-κ B复合物在功能上相互作用。我们认为CBP通过ER α靶向导致NF-κ B的抑制，并且可能通过依赖于ER α配体性质的转录惰性多聚体复合物的形成而发生。
Functional interactions or cross-talk between ligand-activated nuclear receptors and the proinflammatory transcription factor nuclear factor-kappa B (NF-kappa B) may play a major role in ligand-mediated modification of diseases processes. In particular, the cardioprotective effects of estrogen replacement therapy are thought to be due in part to the ability of ligand-bound estrogen receptor (ER) to inhibit NF-kappa B function. In the current study 17 beta-estradiol-bound ER alpha interfered with cytokine-induced activation of a NF-kappa B reporter in HepG2 cells. The estrogen metabolite, 17 alpha-ethinyl estradiol, and the phytoestrogen, genistein, were also effective inhibitors of NF-kappa B activation, whereas tamoxifen, 4-hydroxytamoxifen, and raloxifene were inactive. This inhibition was reciprocal, as NF-kappa B interfered with the trans-activation properties of ER alpha. Ligand-bound ER alpha did not inhibit NF-kappa B binding to DNA, but it did decrease the histone acetyltransferase activity required for NF-kappa B transcriptional activity. Coexpression of the transcription coactivator CREB binding protein (CBP), but not steroid receptor coactivator 1a, reversed the ER alpha-mediated inhibition of NF-kappa B activity. Mammalian two-hybrid experiments also revealed that ligand-bound ER alpha can interact functionally with CBP-NF-kappa B complexes. We suggest that CBP targeting by ER alpha results in the inhibition of NF-kappa B and may occur through formation of transcriptionally inert multimeric complexes that are dependent upon the nature of the ER alpha ligand.