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Transcriptional regulation of autocrine IL-6 expression in multiple myeloma cells

机译:在多发性骨髓瘤细胞中自分泌IL-6表达的转录调控

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摘要

Multiple myeloma (MM) is an as to date incurable hematopoietic malignancy. The importance of Interleukin-6 (IL-6) as an autocrine growth factor for MM cells is widely accepted, yet very little is known about the mechanisms at the basis of deregulated IL-6 expression in MM cells. Here we show that the in vivo chromatin organization of the IL-6 gene is different in MM cells, that constitutively express IL-6 (U266), as compared to MM cells, in which the IL-6 promoter is inactive (L363). We observed enhanced nuclease accessibility of the the AP-1- and, especially, the Sp1-responsive elements in the IL-6 promoter in U266 cells. Interestingly, we found that Sp1 was eliminated from the IL-6 promoter after treatment with the ERK inhibitor U0126. The importance of ERK and Sp1 in regulating IL-6 transcription was, furthermore, supported by the observation that treatment of U266 cells with U0126 or mithramycin, an antibiotic that prevents Sp1-DNA binding, abrogated constitutive IL-6 transcription. Importantly, the finding that both U0126 and mithramycin were more potent inhibitors of U266 cell viability than the synthetic glucocorticoid drug, dexamethasone, indicates that targeting the Sp1 transcription factor might have therapeutic value in treatment of autocrine MM. (c) 2008 Elsevier Inc. All rights reserved.
机译:迄今为止,多发性骨髓瘤(MM)是无法治愈的造血系统恶性肿瘤。白介素6(IL-6)作为MM细胞自分泌生长因子的重要性已被广泛接受,但对于MM细胞中IL-6表达失控的机制了解甚少。在这里,我们显示,与IL-6启动子失活的MM细胞(L363)相比,IL-6基因的体内染色质组织在组成性表达IL-6(MM266)的MM细胞中有所不同。我们观察到的AP-1-,尤其是U266细胞中IL-6启动子中的Sp1反应元件增强了核酸酶的可及性。有趣的是,我们发现在用ERK抑制剂U0126处理后,Sp1已从IL-6启动子中清除。此外,以下观察结果支持了ERK和Sp1在调节IL-6转录中的重要性:用U0126或光神霉素(一种防止Sp1-DNA结合的抗生素)治疗U266细胞会废除组成型IL-6转录,这一事实得到了支持。重要的是,与合成的糖皮质激素类药物地塞米松相比,U0126和光神霉素均是更有效的U266细胞活力抑制剂,这一发现表明靶向Sp1转录因子在自分泌MM的治疗中可能具有治疗价值。 (c)2008 Elsevier Inc.保留所有权利。

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