Transcriptional regulation of cyclooxygenase-2 in response to proteasome inhibitors involves reactive oxygen species-mediated signaling pathway and recruitment of CCAAT/enhancer-binding protein δ and CREB-binding protein
Transcriptional regulation of cyclooxygenase-2 in response to proteasome inhibitors involves reactive oxygen species-mediated signaling pathway and recruitment of CCAAT/enhancer-binding protein δ and CREB-binding protein
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DOI：
10.1091/mbc.e05-08-0778
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发表时间：
2005-12-01
影响因子：
3.3
通讯作者：
Chen, CC
中科院分区：
文献类型：
--
作者：
Chen, JJ;Huang, WC;Chen, CC
抑制泛素-蛋白酶体途径已被证明是治疗炎症和癌症的一种有前途的策略。在这里，我们发现蛋白酶体抑制剂MG132、PSI-1和lactacystin在人肺泡NCI-H292和A549以及胃AGS上皮细胞中通过增强基因转录而不是阻止蛋白质降解来诱导COX-2表达。COX-2启动子上的NF-IL6和CRE元件参与了基因转录事件，而NF-kappa B元件不参与。MG132增强了CCAAT/增强子结合蛋白(C/EBP) β和C/EBP δ与CRE和NF-IL6元件的结合，以及CBP的募集和COX-2启动子上组蛋白H3和H4乙酰化的增强。但对C/EBP β和C/EBP δ总蛋白水平没有影响。mg132诱导C/EBP δ的dna结合活性，而C/EBP β不受p38、PI3K、Src和蛋白激酶C的调控。C/EBP p5的小干扰RNA抑制COX-2的表达，进一步增强了C/EBP δ在COX-2基因转录中的作用。此外，MG132作用下细胞内活性氧（ROS）的产生促进了MAPKs和Akt的激活。这些发现表明，蛋白酶体抑制剂诱导COX-2转录的诱导需要ros依赖性蛋白激酶的激活和随后的C/EBP δ和CBP的募集。
Inhibition of ubiquitin-proteasome pathway has been shown to be a promising strategy for the treatment of inflammation and cancer. Here, we show that proteasome inhibitors MG132, PSI-1, and lactacystin induce COX-2 expression via enhancing gene transcription rather than preventing protein degradation in the human alveolar NCI-H292 and A549, and gastric AGS epithelial cells. NF-IL6 and CRE, but not NF-kappa B elements on the COX-2 promoter were involved in the gene transcription event. The binding of CCAAT/enhancer binding protein (C/EBP)beta and C/EBP delta to the CRE and NF-IL6 elements, as well as the recruitment of CBP and the enhancement of histone H3 and H4 acetylation on the COX-2 promoter was enhanced by MG132. However, it did not affect the total protein levels of C/EBP beta and C/EBP delta. MG132-induced DNA-binding activity of C/EBP delta, but not C/EBP beta was regulated by p38, PI3K, Src, and protein kinase C. Small interfering RNA of C/EBP5 suppressed COX-2 expression, further strengthening the role of C/EBP delta in COX-2 gene transcription. In addition, the generation of intracellular reactive oxygen species (ROS) in response to MG132 contributed to the activation of MAPKs and Akt. These findings reveal that the induction of COX-2 transcription induced by proteasome inhibitors requires ROS-dependent protein kinases activation and the subsequent recruitments of C/EBP delta and CBP.