Transcriptional regulation of ATP2C1 gene by Sp1 and YY1 and reduced function of its promoter in Hailey-Hailey disease keratinocytes
Transcriptional regulation of ATP2C1 gene by Sp1 and YY1 and reduced function of its promoter in Hailey-Hailey disease keratinocytes
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DOI：
10.1111/j.0022-202x.2005.23748.x
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发表时间：
2005-06-01
影响因子：
6.5
通讯作者：
Ogawa, H
中科院分区：
文献类型：
--
作者：
Kawada, H;Nishiyama, C;Ogawa, H
Hailey-Hailey病（HHD）是一种由Ca 2+依赖性ATP酶（ATP 2C 1）功能障碍引起的水疱性皮肤病。在这项研究中，关键的调控区域所需的基因编码的人ATP 2C 1的表达进行了调查。瞬时报告基因分析表明，+21/+57区域是激活ATP 2C 1启动子所必需的，电泳迁移率变动分析表明，该区域被转录因子Sp1和YY 1识别。根据该结果，当Sp1或YY 1在角质形成细胞中过表达时，观察到ATP 2C 1启动子活性的明显增加，这与缺少Sp1和YY 1的结合位点的突变型启动子用作报道基因的情况相反。Ca ~（2+）刺激信号增加正常角质形成细胞核Sp1蛋白和ATP ~（2 C1）mRNA水平。相反，这两种增加在HHD患者的角质形成细胞中受到抑制。这些结果表明，Sp1和YY 1通过顺式增强元件反式激活人ATP 2C 1启动子，ATP 2C 1转录的不完全上调有助于HHD的角质形成细胞特异性发病机制。这是一份描述ATP 2C 1表达调控的报告。
Hailey-Hailey disease (HHD) is a blistering skin disease caused by malfunction of the Ca2+-dependent ATPase, ATP2C1. In this study, key regulatory regions necessary for the expression of the gene encoding human ATP2C1 were investigated. The transient reporter assay demonstrated that region +21/+57 was necessary for activation of the ATP2C1 promoter, and the electrophoretic mobility shift assay demonstrated that the region was recognized by the transcription factors, Sp1 and YY1. In accordance with this result, when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. Ca2+-stimulation signal increased nuclear Sp1 proteins and ATP2C1 mRNA levels in normal keratinocytes. In contrast, both these increases were suppressed in keratinocytes from HHD patients. These results indicate that Sp1 and YY1 transactivate the human ATP2C1 promoter via cis-enhancing elements and that incomplete upregulation of ATP2C1 transcription contributes to the keratinocyte-specific pathogenesis of HHD. This is a report describing the regulation of the expression of ATP2C1.