12q21.33

HH19,MKP3,PYST1

Various cancers

DUSP6 null mice demonstrate enhanced ERK1/2 phosphorylation leading to increased myocyte proliferation and cardiac hypercellularity (Maillet et al., 2008). DUSP6 has been identified as a potential novel tumor suppressor gene in pancreatic cancer since loss of DUSP6 expression might synergize with activating-mutated k-Ras resulting in increased activation of ERK1/2 MAP kinase and thus contribute to the development of the malignant and invasive phenotype in pancreatic cancer (Furukawa et al., 2003). Loss of DUSP6 expression caused by oxidative stress-mediated degradation was also noted in ovarian cancer and correlated with high ERK1/2 activity (Chan et al., 2008). DUSP6 has also been identified as one of only three genes which are uniquely expressed in myeloma cells harboring a constitutively active mutant N-ras gene and is also overexpressed in human melanoma cell lines with potent activating mutations in B-raf and in breast epithelial cells stably expressing H-Ras (Bloethner et al., 2005; Croonquist et al., 2003; Warmka et al., 2004), suggesting that the over-expression of DUSP6 seen in response to activating-mutated Ras or Raf might represent a compensatory increase in the negative feedback control of the ERK1/2 MAPK pathway, which lies downstream of these activated oncogenes. In support of this, the tetracycline-induced expression of a functional fusion protein between DUSP6 and green fluorescent protein in H-ras transformed fibroblasts following injection into nude mice resulted in a large delay in tumor emergence and growth as compared to the untreated control group (Marchetti et al., 2004 ). DUSP6 has been reported to be one of the most highly regulated genes in chronic myeloid leukemia cells upon imatinib treatment (Hakansson et al., 2008) and similarly DUSP6 is overexpressed upon inducible expression of the EGFRvIII oncogene in glioblastoma cells (Ramnarain et al., 2006). DUSP6 has also been demonstrated to be positively correlated with the activity of the oncogenic ERK pathway in non-small cell lung cancer tissue and is an ETS-regulated negative feedback mediator of ERK signaling in lung cancer cells (Zhang et al., 2010).

Elevated DUSP6 RNA expression was reported to be a major negative predictor of survival in patients with resected non-small cell lung cancer as part of a five-gene signature model (Chen et al., 2007).