Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells
Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells
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DOI：
10.1016/j.bbrc.2008.10.003
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发表时间：
2008-12-05
影响因子：
3.1
通讯作者：
Horii, Akira
中科院分区：
文献类型：
--
作者：
Furukawa, Toru;Tanji, Etsuko;Horii, Akira
DUSP 6/MKP-3是一种双特异性磷酸酶，其底物识别和去磷酸化活性仅特异于MAPK 1/ERK 2。DUSP 6被证明以反馈回路的方式在MAPK 1中发挥负调控作用：然而，其在人类细胞中表达的调控机制在很大程度上是未知的。我们以前发现，人胰腺癌细胞经常丢失DUSP 6的表达，这可以诱导组成型活性MAPK 1，这种丢失与DUSP 6内含子I的CpG簇区域的高甲基化有关。在这项研究中，我们研究了DUSP 6的内含子I在人类细胞中的启动子活性。我们证明了内含子确实具有启动子活性，并且这种活性与MAPK 1活性相关。此外，启动子活性依赖于ETS转录因子的共有结合序列，ETS 2与内含子特异性相关。由于ETS 2是MAPK的直接靶点，这些结果表明DUSP 6的内含子1在人细胞中以反馈环方式响应MAPK I经由ETS 2在DUSP 6的转录调控中起关键作用。(C)2008年爱思唯尔公司All rights reserved. L
DUSP6/MKP-3 is a dual Specificity phosphatase exclusively specific to MAPK1/ERK2 for its substrate recognition and dephosphorylating activity. DUSP6 is demonstrated to play a negative regulatory role in MAPK1 in a feedback loop manner: however, the regulation mechanisms of its expression in human cells have been largely unknown. We Previously found that human pancreatic cancer cells frequently lost DUSP6 expression, which could induce Constitutively active MAPK1, and the loss was associated with hypermethylation of the CpG cluster region of intron I of DUSP6. In this study, we investigated the promoter activity of intron I of DUSP6 in human cells. We demonstrated that the intron indeed had promoter activity and this activity was associated with MAPK1 activity. Moreover, promoter activity depended on a consensus binding sequence of ETS transcription factors and ETS2 was specifically associated with the intron. Because ETS2 is a direct target of MAPK, these results indicate that intron 1 of DUSP6 plays a crucial role in transcriptional regulation of DUSP6 in a feedback loop manner responding to MAPK I via ETS2 in human cells. (C) 2008 Elsevier Inc. All rights reserved. l