Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor.
Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor.
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DOI：
10.1002/eji.201646315
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发表时间：
2016-10
影响因子：
5.4
通讯作者：
Zhang, Xian K.
中科院分区：
文献类型：
--
作者：
Richard, Mara L. Lennard;Brandon, Danielle;Lou, Ning;Sato, Shuzo;Caldwell, Tomika;Nowling, Tamara K.;Gilkeson, Gary;Zhang, Xian K.
Fli-1已成为炎症介质（包括MCP-1、CCL 5和IL-6）的关键调节剂。细胞因子粒细胞集落刺激因子（G-CSF）调节中性粒细胞前体成熟和存活，并激活成熟的中性粒细胞。此前，观察到Fli-1+/−狼疮易感小鼠肾脏中的中性粒细胞浸润显著减少。在这项研究中，一个显着减少G-CSF蛋白的表达被检测到在刺激的小鼠和人的内皮细胞时，Fli-1的表达被抑制。鼠G-CSF启动子含有许多推定的Fli-1结合位点，并且近端启动子内的几个区域显著富集Fli-1结合。瞬时转染试验表明，Fli-1驱动转录从G-CSF启动子和突变的Fli-1 DNA结合结构域导致94%的转录激活的损失。已知乙酰化位点的突变导致G-CSF启动子激活显著增加。组蛋白乙酰转移酶p300/CBP和p300/CBP相关因子（PCAF）显著降低G-CSF启动子的Fli-1特异性激活。因此，乙酰化似乎是Fli-1驱动的G-CSF启动子激活背后的重要机制。这些结果进一步支持了Fli-1在调节几种炎症介质中起主要作用，最终影响炎症性疾病发病机制的理论。
Fli-1 has emerged as a critical regulator of inflammatory mediators, including MCP-1, CCL5, and IL-6. The cytokine, granulocyte colony stimulating factor (G-CSF) regulates neutrophil precursor maturation and survival, and activates mature neutrophils. Previously, a significant decrease in neutrophil infiltration into the kidneys of Fli-1+/− lupus-prone mice was observed. In this study, a significant decrease in G-CSF protein expression was detected in stimulated murine and human endothelial cells when expression of Fli-1 was inhibited. The murine G-CSF promoter contains numerous putative Fli-1 binding sites and several regions within the proximal promoter are significantly enriched for Fli-1 binding. Transient transfection assays indicate that Fli-1 drives transcription from the G-CSF promoter and mutation of the Fli-1 DNA binding domain resulted in a 94% loss of transcriptional activation. Mutation of a known acetylation site, led to a significant increase in G-CSF promoter activation. The histone acetyltransferases p300/CBP and p300/CBP associated factor (PCAF) significantly decrease Fli-1 specific activation of the G-CSF promoter. Thus, acetylation appears to be an important mechanism behind Fli-1 driven activation of the G-CSF promoter. These results further support the theory that Fli-1 plays a major role in the regulation of several inflammatory mediators, ultimately affecting inflammatory disease pathogenesis.
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影响因子：
3.7
作者：
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通讯作者：
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作者：
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通讯作者：
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