Glucocorticoid repression of AP-1 is not mediated by competition for nuclear coactivators
Glucocorticoid repression of AP-1 is not mediated by competition for nuclear coactivators
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DOI：
10.1210/me.15.2.219
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发表时间：
2001-02-01
影响因子：
--
通讯作者：
Haegeman, G
中科院分区：
文献类型：
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作者：
De Bosscher, K;Vanden Berghe, W;Haegeman, G
白细胞介素-6（IL-6）是一种多效性细胞因子，参与许多自身免疫性和炎症性疾病。IL-6基因表达的转录控制由各种化合物发挥，其中糖皮质激素是目前使用的最有效的免疫抑制剂。糖皮质激素通过负性干扰转录因子如核因子-κ B（NF-κ B）和AP-1发挥反式阻遏作用。这两种因子都利用共激活因子cAMP反应元件结合蛋白（CREB）结合蛋白（CBP）来增强它们的转录活性，这导致了一种假设，即p65或c-Jun与活化的糖皮质激素受体（GR）之间的相互拮抗作用是由有限量的CBP引起的。最近，我们发现糖皮质激素抑制NF-κ B驱动的基因表达的发生与细胞中辅激活因子水平的量无关。在目前的研究中，我们扩展了这一观察，并证明了糖皮质激素对AP-1靶向基因的抑制对核辅激活因子的增加是难治的。从Gal 4嵌合蛋白的结果中，我们得出结论，糖皮质激素抑制发生的启动子独立的机制，涉及激活的GR和AP-1之间的核相互作用，独立于CBP水平的细胞。
Interleukin-6 (IL-6) is a pleiotropic cytokine that is involved in many autoimmune and inflammatory diseases. Transcriptional control of IL-6 gene expression is exerted by various compounds, among which glucocorticoids are the most potent antiinflammatory and immunosuppressive agents currently in use. Glucocorticoids exert their transrepressive actions by negatively interfering with transcription factors, such as nuclear factor-kappaB (NF-kappaB) and AP-1. Both factors make use of the coactivator cAMP response element-binding protein (CREB)-binding protein (CBP) to enhance their transcriptional activities, which led to the hypothesis that a mutual antagonism between p65 or c-Jun and activated glucocorticoid receptor (GR) results from a limited amount of CBP. Recently, we showed that glucocorticoid repression of NF-kappaB-driven gene expression occurs irrespective of the amount of coactivator levels in the cell. In the current study, we extend this observation and demonstrate that also AP-1-targeted gene repression by glucocorticoids is refractory to increased amounts of nuclear coactivators. From results with Gal4 chimeric proteins we conclude that glucocorticoid repression occurs by a promoter-independent mechanism involving a nuclear interplay between activated GR and AP-1, independently of CBP levels in the cell.