DUSP6/MKP-3/PYST1 is a dual specificity phosphatase exclusively specific to MAPK1/ERK2/ERK for its substrate recognition and dephosphorylating activity [1] and [2]. DUSP6 has been demonstrated to be a negative feedback regulator of MAPK1 [3], [4] and [5]; however, the regulation mechanisms of its expression in human
AUY922 have been largely unknown. The encoding gene, DUSP6, is located on 12q21-q22, the region commonly deleted hemizygously in pancreatic cancer [6] and [7]. DUSP6 is frequently underexpressed in pancreatic ductal adenocarcinoma although it is overexpressed in pancreatic intraepithelial neoplasia, one of precursor lesions of ductal adenocarcinoma [8]. Its underexpression is associated with constitutive activation of MAPK1 [9]. Exogenous overexpression of DUSP6 in DUSP6-abrogated pancreatic cancer
cells results in inactivation of MAPK1 and eventual apoptosis [9]. This evidence indicates that pancreatic cancer cells losing DUSP6 expression are addicted to active MAPK1 for their survival and proliferation, and that DUSP6 plays an antagonistic role in this addiction; hence, a tumor suppressive role. The underexpression of DUSP6 in pancreatic ductal adenocarcinoma is associated with the hypermethylation of CpG cluster region of intron 1 of DUSP6 [10], which suggest that the intron may be a key control region for DUSP6 expression. In this study, we investigated the expression mechanism of DUSP6 by examining the promoter activity of intron 1 of DUSP6 in human cells.
