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首页> 外文期刊>Pharmacological research: The official journal of The Italian Pharmacological Society >Erythroid induction of K562 cells treated with mithramycin is associated with inhibition of raptor gene transcription and mammalian target of rapamycin complex 1 (mTORC1) functions
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Erythroid induction of K562 cells treated with mithramycin is associated with inhibition of raptor gene transcription and mammalian target of rapamycin complex 1 (mTORC1) functions

机译：用Mithramycin处理的K562细胞的红细胞诱导与Raptor基因转录和哺乳动物催乳素复合物1（MTORC1）功能的抑制相关

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Rapamycin, an inhibitor of mTOR activity, is a potent inducer of erythroid differentiation and fetal hemoglobin production in beta-thalassemic patients. Mithramycin (MTH) was studied to see if this inducer of K562 differentiation also operates through inhibition of mTOR. We can conclude from the study that the mTOR pathway is among the major transcript classes affected by mithramycin-treatment in K562 cells and a sharp decrease of raptor protein production and p70S6 kinase is detectable in mithramycin treated K562 cells. The promoter sequence of the raptor gene contains several Sp1 binding sites which may explain its mechanism of action. We hypothesize that the G + C-selective DNA-binding drug mithramycin is able to interact with these sequences and to inhibit the binding of Sp1 to the raptor promoter due to the following results: (a) MTH strongly inhibits the interactions between Sp1 and Sp1-binding sites of the raptor promoter (studied by electrophoretic mobility shift assays, EMSA); (b) MTH strongly reduces the recruitment of Sp1 transcription factor to the raptor promoter in intact K562 cells (studied by chromatin immunoprecipitation experiments, ChIP); (c) Sp1 decoy oligonucleotides are able to specifically inhibit raptor mRNA accumulation in K562 cells. In conclusion, raptor gene expression is involved in mithramycin-mediated induction of erythroid differentiation of K562 cells and one of its mechanism of action is the inhibition of Sp1 binding to the raptor promoter. (C) 2014 The Authors. Published by Elsevier Ltd.
机译：MTOR活性抑制剂的雷帕霉素是β-脑血病患者的红细胞分化和胎儿血红蛋白产生的有效诱导剂。研究了Mithramycin（MTH），看看该K562分化的诱导剂还能通过抑制mTor来运作。我们可以从研究中得出结论，MTOR途径是K562细胞中的Mithramycin治疗影响的主要转录类别，并且在Mithramycin处理的K562细胞中检测到猛禽蛋白质产生和P70S6激酶的急剧下降。猛杆基因的启动子序列含有几个SP1结合位点，其可以解释其作用机制。我们假设G + C选择性DNA结合药物Mithramycin能够与这些序列相互作用，并且由于以下结果，抑制SP1与猛禽启动子的结合：（a）Mth强烈抑制SP1和SP1之间的相互作用 - 猛禽启动子的困扰点（通过电泳迁移率转移测定，EMSA研究）; （b）MTH强烈减少了在完整的K562细胞中募集到猛禽启动子的SP1转录因子（通过染色质免疫沉淀实验，芯片研究）; （c）SP1诱饵寡核苷酸能够特异性地抑制K562细胞中的猛杆mRNA积累。总之，猛禽基因表达涉及Mithramycin介导的K562细胞红霉分化的诱导，其作用机制之一是抑制SP1与猛禽启动子的结合。 （c）2014年作者。 elsevier有限公司出版

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