Disease relevance of DUSP6

• Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer [1].
• In pancreata with intraductal papillary-mucinous neoplasms, abrogated expressions of DUSP6 were observed in a relatively small fraction of intraductal adenoma/borderlines and intraductal carcinomas [2].
• In pancreata with invasive ductal carcinomas, expressions of DUSP6 were abrogated exclusively in the invasive carcinoma cells in contrast to its fairly preserved expressions in pancreatic intraepithelial neoplasia [2].
• Methylation was detected in five of eight cases with abolished expressions of DUSP6, four of which were poorly differentiated adenocarcinoma [3].
• Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance [4].

Psychiatry related information on DUSP6

• Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler [5].
• The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder [6].

High impact information on DUSP6

• MKP-3 was activated by direct binding to purified ERK2 [7].
• MAP kinase phosphatase-3 (MKP-3) dephosphorylates phosphotyrosine and phosphothreonine and inactivates selectively ERK family mitogen-activated protein (MAP) kinases [7].
• MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain [8].
• Furthermore, unlike the nuclear CL100 protein, Pyst1 is localized in the cytoplasm of transfected Cos-1 cells [9].
• In addition, Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells [9].

Chemical compound and disease context of DUSP6

• DUSP6 (alias PYST1), one of the dual-specificity tyrosine phosphatases, is localized on 12q21, one of the regions of frequent allelic loss in pancreatic cancer [10].

Biological context of DUSP6

• These results show that DUSP6 exerts apparent tumor-suppressive effects in vitro and suggest that DUSP6 is a strong candidate tumor suppressor gene at 12q22 locus [1].
• On the other hand, none of the four cases with preserved expression of DUSP6 showed methylation [3].
• These results indicate that hypermethylation of the CpG islands in intron 1 may account for the strong suppression of DUSP6 expression [3].
• However, two cell lines with up-regulation of the PI3K/AKT cascade also had up-regulation in the RAS/MAPK cascade induced by inactivation of DUSP6 [11].
• Finally, we show that the phosphorylation of MKP-3 has no effect on its catalytic activity [12].

Anatomical context of DUSP6

• First, we checked intrinsic transcriptional expression levels of DUSP6 by a quantitative real time PCR assay in 16 cultured pancreatic cancer cell lines and found that the cells could be classified into four groups: very-low-level expression, low-level expression, high-level expression, and very-high-level expression [3].
• Pyst1 is expressed constitutively in human skin fibroblasts and, in contrast to other members of this family of enzymes, its mRNA is not inducible by either stress or mitogens [9].
• We found that 308 keratinocytes highly express mitogen-activated protein kinase phosphatase-3 (MKP-3), which selectively inactivates ERK [13].
• MKP-1, but not MKP-3, mRNA expression was 10-fold up-regulated in both mouse and human osteoblast cell lines within 30 min of Dex treatment and remained elevated for 24 h [14].
• Angiotensin II-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis [15].

Associations of DUSP6 with chemical compounds

• Using a sodium-bisulfite-modification assay, we found that CpG sequences in intron 1 of DUSP6 were heavily methylated in MIA PaCa-2 and PAN07JCK, both showing the very low level of intrinsic expression of the gene [3].
• We observed restored expression of DUSP6 after treatment with 5-azacytidine and trichostatin A, a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, respectively, in cells with intrinsically very-low-level and low-level expression of DUSP6 [3].
• Accumulation of reactive oxygen species was observed with tamoxifen treatment of MKP3-overexpressing cells, and antioxidant treatment increased MKP3 phosphatase activity, thereby blocking resistance [4].
• Furthermore, the nuclear translocation of MKP-3 seen in the presence of leptomycin B is mediated by an active process, indicating that MKP-3 shuttles between the nucleus and cytoplasm [16].
• The amino-terminal noncatalytic domain of MKP-3 is both necessary and sufficient for nuclear export of the phosphatase and contains a single functional leucine-rich nuclear export signal (NES) [16].

Physical interactions of DUSP6

• A third ERK2 binding site is localized in the C terminus of MKP3 (residues 348--381) [17].

Enzymatic interactions of DUSP6

• In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197 [12].

Regulatory relationships of DUSP6

• Furthermore, U0126 inhibited EGF-induced MKP-3 and MKP-1 protein expression [18].
• Transfection with a dominant negative MKP-3 construct (dnMKP-3mt) prevented the Ang II-induced ERK1/2 dephosphorylation and apoptosis in EC (p < 0.001) [15].

Other interactions of DUSP6

• This reinforces the conclusion that Pyst1 and Pyst2 are members of a distinct and structurally homologous subfamily of dual-specificity (Thr/Tyr) MAP kinase phosphatases [19].
• Most of the intraductal adenoma/borderline lesions with abrogation of DUSP6 harbored mutations of KRAS2 [2].
• Gene expression profiling was used to identify mitogen-activated protein kinase (MAPK) phosphatase 3 (MKP3) whose expression was correlated with response to the antiestrogen tamoxifen in both patients and in vitro-derived cell line models [4].
• MKP3 represents a novel mechanism of resistance, which may be a potential biomarker for the use of ERK1/2 and/or JNK inhibitors in combination with tamoxifen treatment [4].
• Overexpression of MKP3 rendered ER-alpha-positive breast cancer cells resistant to the growth-inhibitory effects of tamoxifen and enhanced tamoxifen agonist activity in endometrial cells [4].

Analytical, diagnostic and therapeutic context of DUSP6

• We checked the methylation state of this region by a methylation-specific PCR method in 12 primary pancreatic cancer tissues and compared it with the expression state of DUSP6 investigated by immunohistochemistry [3].
• In situ hybridization studies of MKP-3 in brain reveal enrichment within the CA1, CA3, and CA4 layers of the hippocampus [20].
• Microinjection of active mammalian MAP kinase phosphatase (MKP-3) resulted in inactivation of MAP kinase in unfertilized eggs, as did addition of MKP-3 to lysates of unfertilized eggs [21].

References