The human DUSP1 gene spans 3111 bases, telomere to centromere orientation.

The human DUSP1 gene is located on chromosome 5q35.1 and consists of 4 exons separated by three relatively small introns (400-500 bp) (Figure 2). The full length coding sequence of DUSP1 contains 2019 nucleotides. The human DUSP1 gene contains four exons and three introns coding for an inducible mRNA with an approximate size of 2.4 kb (Kwak et al., 1994). The first domain which is located towards the C-terminus (Exon 4) contains the active site motif common to all PTPases, and the second domain (termed CH2) resides at the N-terminus (exons 1-2) and exhibits two segments of similarity to the region surrounding the Cdc25 active site.

Studies using northern blots have shown that high levels of DUSP1 mRNA were detected in lung, liver, placenta, and pancreas whereas moderate levels of DUSP1 mRNA were found in the heart and skeletal muscle (Kwak et al., 1994). Low levels were detected in the brain and kidney. Nevertheless, an abundance of factors can upregulate DUSP1 mRNA levels in a variety of cell types. DUSP1 is a transcriptional target of p53 which binds to the p53 binding site located in the second intron which was first shown in a human glioblastoma cell line (Li et al., 2003). DUSP1 is also upregulated in response to a variety of cellular stress conditions including oxidative stress and DNA damaging agents in human skin cells (Keyse and Emslie, 1992). DUSP1 mRNA is also upregulated in response to hypoxia at levels found in solid tumours (Laderoute et al., 1999). A strong induction of the DUSP1 gene was seen in neuroendocrine cells by thyrotropin-releasing hormone (TRH) and epidermal growth factor (EGF) (Ryser et al., 2001; Ryser et al., 2002).
The initial 1 kb region upstream of exon 1 in the DUSP1 promoter contains elements important for the control of DUSP1 transcription (Figure 3). However, as well as a TATA box, an E-box and 2 conserved and functionally important ATF binding sites, this region also contains three GC boxes and an NF1 site (Kwak et al., 1994; Pursiheimo et al., 2002; Ryser et al., 2004; Kristiansen et al., 2010). The two ATF sites have been shown to bind c-Jun and ATF2 which is important for the activation of DUSP1 transcription by the JNK pathway following survival factor withdrawal in neurons (Kristiansen et al., 2010).

There are no known pseudogenes for DUSP1.

DUSP family members share a common structure comprising a C-terminal cysteine-dependent protein tyrosine phosphatase active site sequence (Camps et al., 2000). The structure of DUSP proteins confers phosphatase activity for both phospho-serine/threonine and phospho-tyrosine residues. The non-catalytic N-terminal region contains a rhodanese domain which is known to catalyse a sulphur transfer reaction. Also in this domain are two regions of homology with sequences flanking the active site of the Cdc25 cell cycle regulatory phosphatase (Keyse and Ginsberg, 1993). The full-length human DUSP1 protein (Transcript variant 1) contains 367 amino acids and has a molecular weight of 39 kDa (Figure 4). Two further transcripts have been described. Transcript variant 2 codes for a shorter protein of 302 amino acids with a molecular weight of 32 kDa. Transcript variant 3 encodes for a protein of 340 amino acids with a molecular weight of 36 kDa.

Increases in DUSP1 protein expression have been seen in a variety of cell types in response to various signals (Table 1) such as EGF-treated mouse embryonic fibroblasts (Wu and Bennett, 2005) and NGF-deprived rat sympathetic neurons (Kristiansen et al., 2010). The half life of DUSP1 has been found to vary between 40 and 120 minutes (Charles et al., 1992; Noguchi et al., 1993).

DUSP1 is primarily a nuclear dual specificity protein phosphatase.

Mitogen activated protein kinases (MAPK) are a family of kinases that include the extracellular signal regulated kinases (ERKs), p38 and c-Jun NH2-terminal kinase (JNKs). They play an important role in regulation and are activated by a number of stimuli such as growth factors, cytokines or stress conditions. This in turn regulates a variety of processes including proliferation, apoptosis, survival and the production of inflammatory molecules. As a result the regulation of MAPKs is important and so an equilibrium between the activation of MAPKs and their deactivation is vital.
Dual-specificity phosphatases (DUSP) are a large family of phosphatases that include the subset of MAPK phosphatases (MKPs). In particular, DUSP1 is a nuclear mitogen-activated protein kinase (MAPK) phosphatase with substrate specificity for p38 kinases and JNKs and to a lesser extent ERK (Franklin and Kraft, 1997; Camps et al., 2000; Farooq and Zhou, 2004) and functions by dephosphorylating the phospho-threonine and phospho-tyrosine residues located in the activation loop of their target substrates (Patterson et al., 2009) to negatively regulate MAPK signalling (Sun et al., 1993; Keyse, 2000; Kristiansen et al., 2010).
DUSP1 is a negative regulator of cellular proliferation but also has other functions such as the regulation of cytokine biosynthesis in response to bacterial lipopolysaccharide (LPS) (Huang et al., 2011). DUSP1 plays a significant role in immune regulation (reviewed in Wancket et al., 2012) and it has been shown that the half lives of several cytokines can be reduced by the overexpression of DUSP1 mRNA (Yu et al., 2011a). DUSP1 has also been shown to play a part in mediating the anti-inflammatory response to glucocorticoids (Chi et al., 2006; Hammer et al., 2005; Abraham et al., 2006; Zhao et al., 2006). DUSP1 has an important role in metabolic homeostasis, as studies have shown that mice lacking the DUSP1 gene are resistant to obesity induced by a high fat diet (Zhang et al., 2004). Furthermore, DUSP1 can play a role in altering lipid metabolism in multiple tissues when a high fat diet is consumed (Flach et al, 2011; Wu et al., 2006). DUSP1 protects mice from lethal endotoxic shock (Hammer et al., 2006) and it has also been shown that DUSP1 can protect the oral cavity against inflammation triggered by bacterial ligands (Sartori et al., 2009; Yu et al., 2011b). In rodent stroke models, DUSP1 overexpression has been shown to suppress neuronal death in a negative feedback manner (Koga et al., 2012).

DUSPs contain two regions of homology with the cell cycle regulatory phosphatase Cdc25 in their NH2-terminal domain. A conserved catalytic domain in the C-terminal region, contains an active site with a sequence related to the VH-1 DUSP encoded by the vaccina virus. A kinase interactive motif (KIM) also resides in the NH2 terminal domain. This conserved cluster of basic amino acids distinguishes the specificity of MPKs for their MAPK targets. A localisation sequence is also found in the NH2 terminal domain and this determines their cellular localisation. These differences give rise to three groups based on their sequence similarity, structure, substrate specificity and localisation. DUSP1 along with DUSP2, DUSP4 and DUSP5 are known as inducible nuclear phosphatases (Keyse, 2008). DUSP6, DUSP7 and DUSP9 are the closely related ERK-specific and cytoplasmic MKPs whilst DUSP8, DUSP10 and DUSP16 preferentially inactivate p38 and JNK MAP kinases (Keyse, 2008).

A SNP in the DUSP1 gene was identified in intron 1 in a Japanese subpopulation but because this polymorphic site is not within a coding region, it is not likely to influence the function of the gene product (Suzuki et al., 2001).