Transcriptional control of human T-BET expression:: The role of Sp1
Transcriptional control of human T-BET expression:: The role of Sp1
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DOI：
10.1002/eji.200737088
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发表时间：
2007-09-01
影响因子：
5.4
通讯作者：
Caligiuri, Michael A.
中科院分区：
文献类型：
--
作者：
Yu, Jianhua;Wei, Min;Caligiuri, Michael A.
鼠T-bet（在T细胞中表达的T-box）是NK和T细胞中IFN-γ基因表达的主要调节剂。T-bet在自身免疫、哮喘和其他疾病中也起着关键作用。然而，顺式元件或负责调节T-bet表达的反式因子在很大程度上仍然未知。在这里，我们报告我们发现的6个Sp1结合位点内的近端人类T-BET启动子，是高度保守的哺乳动物物种。电泳迁移率变动分析表明，Sp1和近端T-BET启动子之间的物理关联与Sp1表达和T-BET启动子活性之间的直接剂量反应。Sp1的异位过表达也增强了NK细胞和T细胞中的T-BET表达和IFN-γ分泌。光神霉素A阻断了Sp1与T-BET启动子的结合，减少了单核因子刺激的原代人NK细胞中T-BET表达和IFN-γ蛋白的产生。总的来说，我们的研究结果表明，Sp1是一个积极的转录调节T-BET。由于T-BET和IFN-γ在炎症，感染和炎症中至关重要。靶向Sp1的癌症，可能使用光神霉素A，可用于预防和/或治疗与异常T-BET或IFN-γ表达相关的疾病。
Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-gamma gene expression in NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-gamma secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-gamma protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-gamma are critically important in inflammation, infection, and. cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/ or treating diseases associated with aberrant T-BET or IFN-gamma expression.