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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
DUSP1 (dual specificity phosphatase 1)
Mark Kristiansen
Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, 30 Guilford Street,
London WC1N 1EH, UK (MK)
Published in Atlas Database: May 2012
Online updated version :
DOI: 10.4267/2042/48225
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
full length coding sequence of DUSP1 contains 2019
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 Cterminus (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.
Other names: CL100, HVH1, MKP-1, MKP1,
HGNC (Hugo): DUSP1
Location: 5q35.1
Local order: The DUSP1 gene is flanked by the gene
ERGIC1 (upstream) and the NEURL1B gene
(downstream) in the plus strand direction according to
Ensembl annotation.
DUSP1 is a MAPK phosphatase and is a member of the
subfamily of dual specificity phosphatases (DUSPs).
These phosphatases can inactivate MAP kinases by
dephosphorylating both phospho-threonine and
phospho-tyrosine residues located in the activation
loop. DUSP1 is the canonical MAPK phosphatase and
is an immediate early gene. DUSP1 mRNA levels
increase in response to many factors depending on the
cell type, including heat shock and oxidative stress
(Keyse and Emslie, 1992; Franklin et al., 1998), UV
light (Franklin et al., 1998), and survival factor
withdrawal (Kristiansen et al., 2010). DUSP1 knockout
mice have no overt phenotype from histology to
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.,
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 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
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11)
DUSP1 (dual specificity phosphatase 1)
Kristiansen M
Figure 1. Genomic context of the human DUSP1 gene. Figure 1 shows the location of DUSP1 on chromosome 5 which is located
between the NEURL1B and ERGIC1 genes. Arrows indicate the 5' to 3' orientation of each gene. Adapted from the NCBI Map Viewer.
Figure 2. Structure of the human DUSP1 gene and its variants. The full length human DUSP1 transcript (Variant1) is 2019
nucleotides long and consists of four exons separated by three introns of 400-500 bp. The DUSP1 gene is approximately 3.8 kb from the
putative transcription initiation site to the end of exon 4. The 5' untranslated region (5' UTR) and the putative translational start site
(ATG) can be found in exon 1. The non-catalytic region homologous to Cdc25, also known as the CH2 domain, is represented by the
blue regions and is found in exons 1 and 2. Exon 4 contains the sequence encoding the active site cysteine for PTPase activity (orange
region) and also contains > 660 nt of 3' UTR and the polyadenylation signal (AATAA). According to Ensembl, there are two other DUSP1
variants with transcript lengths of 1394 bp (Variant2) and 1854 bp (Variant3).
Figure 3. Alignment of the promoter sequences for the rat and human DUSP1 genes. There are two conserved, potential ATF
binding sites in the DUSP1 promoter. ATF site 1 is located at position 172 to 165 in relation to the transcriptional start site and is one
base different from the ATF/CRE consensus site. ATF site 2, is located at position 124 to 117 and is an exact match for the ATF/CRE
consensus site. A TATA box and a conserved E box are also highlighted. * represent bases conserved between the human and rat gene.
The transcriptional start site of the DUSP1 gene in each species is indicated by an arrow. Adapted from Kristiansen et al., 2010.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11)
DUSP1 (dual specificity phosphatase 1)
Kristiansen M
Figure 4. The structural features of the DUSP1 protein. The highly conserved C-terminal domain of DUSP1 contains the catalytic and
stabilisation and destabilisation domains of the protein. The catalytic domain contains the active site sequence for the dephosphorylation
of tyrosine/threonine residues of target substrates. The N-terminal domain of DUSP1 is mainly responsible for nuclear localisation
through its leucine-rich nuclear targeting sequence (LXXLL) (Wu et al., 2005) and the binding of MAPK through its specific arginine-rich
kinase binding domain. According to UniProtKB/Swiss-Prot, the catalytically inactive rhodanese domain is located within residues 20-137.
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).
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.,
DUSP1 is primarily a nuclear dual specificity protein
There are no known pseudogenes for DUSP1.
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 phosphothreonine 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).
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 Nterminal 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.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11)
DUSP1 (dual specificity phosphatase 1)
Kristiansen M
Table 1. Regulation of DUSP1 expression levels. Table 1 shows a some examples of how DUSP1 protein expression levels can be
increased in a range of cell types in response to various signals.
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).
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
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).
Implicated in
Various cancers
DUSPs contain two regions of homology with the cell
cycle regulatory phosphatase Cdc25 in their NH2terminal 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.
MAP kinase activities impinge on many of the
processes involved in the initiation and genesis of
cancer and therefore abnormalities in MAPK signalling
pathways have been implicated in a wide range of
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11)
DUSP1 (dual specificity phosphatase 1)
Kristiansen M
human malignancies, such as cancer of the colon,
prostate, bladder, ovary, breast and also in NSCLC.
DUSP1 has conflicting roles depending upon the level
of its expression which has been seen to be increased in
early stages of cancer of the prostate, bladder and colon
but whose level decreases at later stages.
Conversely, downregulation of DUSP1 could increase
apoptosis. Pharmacological targeting of DUSP1 could
be considered as a useful tool for improving cancer
treatments and maintaining metabolic homeostasis
(Flach et al., 2012).
Non-small cell lung cancer (NSCLC)
In NSCLC, DUSP1 protein levels are increased (Vicent
et al., 2004; Lim et al., 2003). The localisation of
DUSP1 is predominantly in the nucleus in NSCLC
tumour tissue compared to normal bronchial epithelium
where the protein is localised in both the cytoplasm and
the nucleus. DUSP1 overexpression increased
resistance to cisplatin, a drug which can be used to treat
the disease (Wang et al., 2006).
Other cancers
Human epithelial tumours
An increase in the level of DUSP1 protein has also
been shown in gastric adenocarcinoma (Bang et al.,
1998). In nude mice, downregulation of DUSP1
expression leads to a reduction of tumorigenicity of
pancreatic cancer cells (Liao et al., 2003). Interestingly,
in hepatocellular carcinoma, DUSP1 levels are
decreased which could suggest an opposite role for
DUSP1 in tumour progression (Tsujita et al., 2005). In
lung squamous cell carcinoma (SCC), it has been
reported that levels of DUSP1 expression decrease with
cancer progression (Wang et al., 2011). DUSP1 is
upregulated by hypoxia, which is seen in many grown
tumours (Brahimi-Horn et al., 2007).
In human epithelial tumours (colon, bladder and
prostate), early studies have shown an increase in the
DUSP1 mRNA in the early stages of the disease (Loda
et al., 1996). Interestingly, DUSP1 mRNA
overexpression falls as the tumour becomes more
aggressive and hence with disease progression and was
confirmed in transcriptional profiling studies (Zhang et
al., 1997).
In prostate cancer an increase in DUSP1 levels showed
inverse correlation with JNK activity and apoptotic
markers suggesting that DUSP1 could be anti-apoptotic
(Magi-Galuzzi et al., 1997; Magi-Galuzzi et al., 1998).
overexpressing DUSP1 are resistant to apoptosis
induced by Fas-ligand (Srikanth et al., 1999).
Charles CH, Abler AS, Lau LF. cDNA sequence of a growth
factor-inducible immediate early gene and characterization of
its encoded protein. Oncogene. 1992 Jan;7(1):187-90
Ovarian cancer
Varying levels of DUSP1 protein expression have been
seen in a range of models of ovarian cancer. In low
grade malignant tumours, the level of DUSP1 protein
expression was reduced when compared with benign
cysts and normal surface epithelium. Conversely, in
primary ovarian tumours, moderate to strong
expression of DUSP1 was detected in almost 60% of
invasive ovarian cancers and there was a significant
correlation between DUSP1 expression and a shorter
progressive free survival (Denkert et al., 2002).
Keyse SM, Emslie EA. Oxidative stress and heat shock induce
a human gene encoding a protein-tyrosine phosphatase.
Nature. 1992 Oct 15;359(6396):644-7
Keyse SM, Ginsburg M. Amino acid sequence similarity
between CL100, a dual-specificity MAP kinase phosphatase
and cdc25. Trends Biochem Sci. 1993 Oct;18(10):377-8
Noguchi T, Metz R, Chen L, Mattéi MG, Carrasco D, Bravo R.
Structure, mapping, and expression of erp, a growth factorinducible gene encoding a nontransmembrane protein tyrosine
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1993 Sep;13(9):5195-205
Breast cancer
Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an
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1993 Nov 5;75(3):487-93
Studies have shown an increase in DUSP1 expression
in the late stages of breast cancer (Loda et al., 1996).
The high levels of DUSP1 correlated with a reduction
in JNK activity.
This could mean that therapeutically targeting DUSP1
would increase JNK activity and hence pro-apoptotic
signals in malignant cells (Wang et al., 2003).
Studies show that DUSP1 overexpression decreases
JNK activity whilst DUSP1 knockdown using siRNA
enhanced JNK activity (Small et al., 2007). Recently, it
has been shown in human T47D breast cancer cells that
DUSP1 is a target gene for Progesterone Receptor (PR)
and may have a role in its anti-proliferative and antiinflammatory actions (Chen et al., 2011).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11)
Kwak SP, Hakes DJ, Martell KJ, Dixon JE. Isolation and
characterization of a human dual specificity protein-tyrosine
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human epithelial carcinogenesis. Am J Pathol. 1996
Franklin CC, Kraft AS. Conditional expression of the mitogenactivated protein kinase (MAPK) phosphatase MKP-1
preferentially inhibits p38 MAPK and stress-activated protein
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Magi-Galluzzi C, Mishra R, Fiorentino M, Montironi R, Yao H,
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DUSP1 (dual specificity phosphatase 1)
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