Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells.

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 1 of DUSP6. In this study, we investigated the promoter activity of intron 1 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 MAPK1 via ETS2 in human cells.