p38 mitogen-activated protein kinase inhibits USP22 transcription in HeLa cells
p38 mitogen-activated protein kinase inhibits USP22 transcription in HeLa cells
复制标题
p38 丝裂原激活蛋白激酶抑制 HeLa 细胞中的 USP22 转录。
DOI：
10.3892/br.2015.450
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发表时间：
2015-07-01
影响因子：
2.3
通讯作者：
Li, Weidong
中科院分区：
文献类型：
--
作者：
Xiong, Jianjun;Gong, Zhen;Li, Weidong
泛素特异性加工酶22（USP 22）的高表达在多种类型的人类癌症中被鉴定，并且与肿瘤发生和进展相关。尽管USP 22的生理功能的研究数量增加，但对其表达的调控知之甚少。最近对USP 22基因的5'侧翼序列进行了表征。在本研究中，USP 22的转录受p38丝裂原活化蛋白激酶（MAPK）的调控。用p38 MAPK抑制剂SB 203580处理人宫颈癌（HeLa）细胞，增强了基础USP 22启动子活性和mRNA丰度。MAPK激酶6（MAPK kinase 6，MKK 6）是p38 MAPK的上游激活因子，转染后USP 22 mRNA表达下降40%，而显性失活的MKK 6则增加了USP 22的转录水平，与SB 203580相似。双荧光素酶报告分析表明，转录起始位点之前的Sp1结合位点的突变消除了SB 203580对USP 22启动子的促进作用。顺铂，p38 MAPK的激活剂，也抑制USP 22的表达。这种抑制作用被SB 203580阻断。总之，p38 MAPK在HeLa细胞中作为USP 22转录的上游负调控因子。
Elevated expression of ubiquitin-specific processing enzyme 22 (USP22) was identified in multiple types of human cancers, and was correlated with tumorigenesis and progression. Despite an increase in the numbers of studies in the physiological function of USP22, little is known regarding the regulation of its expression. The 5' flanking sequence of the USP22 gene was recently characterized. In the present study, USP22 transcription was regulated by p38 mitogen-activated protein kinase (MAPK). Treatment of human cervical carcinoma (HeLa) cells with SB203580, an inhibitor of p38 MAPK, enhanced basal USP22 promoter activity and mRNA abundance. Transfection of MAPK kinase 6 (MKK6), an upstream activator of p38 MAPK, resulted in a 40% decrease in USP22 mRNA, while the dominant negative MKK6 increased the transcription level of the USP22, similar to SB203580. Dual luciferase report assays showed that mutations of the Sp1 binding site ahead of the transcription start site abolished the promoting effect of the USP22 promoter by SB203580. Cisplatin, the activator of p38 MAPK, also suppressed USP22 expression. This suppression was blocked by SB203580. In conclusion, p38 MAPK acts as an upstream negative regulator of USP22 transcription in HeLa cells.