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DUSP1 (dual specificity phosphatase 1)

Identity

Other namesCL100
HVH1
MKP-1
MKP1
PTPN10
HGNC (Hugo) DUSP1
LocusID (NCBI) 1843
Location 5q35.1
Location_base_pair Starts at 172195093 and ends at 172198203 bp from pter ( according to hg19-Feb_2009)  [Mapping]
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.
 
  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.
Note 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 behaviour.

DNA/RNA

Note The human DUSP1 gene spans 3111 bases, telomere to centromere orientation.
 
  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.
Description 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.
Transcription 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).
Pseudogene There are no known pseudogenes for DUSP1.

Protein

 
  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.
Description 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.
Expression 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).
 
  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.
Localisation DUSP1 is primarily a nuclear dual specificity protein phosphatase.
Function 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).
Homology 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).

Mutations

Note 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

Entity Various cancers
Note 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 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).
  
Entity Human epithelial tumours
Note 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). Furthermore, human prostate cancer cells overexpressing DUSP1 are resistant to apoptosis induced by Fas-ligand (Srikanth et al., 1999).
  
Entity Ovarian cancer
Note 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).
  
Entity Breast cancer
Note 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 anti-inflammatory actions (Chen et al., 2011).
  
Entity Non-small cell lung cancer (NSCLC)
Note 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).
  
Entity Other cancers
Note 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).
  

External links

Nomenclature
HGNC (Hugo)DUSP1   3064
Cards
AtlasDUSP1ID40371ch5q35
Entrez_Gene (NCBI)DUSP1  1843  dual specificity phosphatase 1
GeneCards (Weizmann)DUSP1
Ensembl (Hinxton)ENSG00000120129 [Gene_View]  chr5:172195093-172198203 [Contig_View]  DUSP1 [Vega]
AceView (NCBI)DUSP1
Genatlas (Paris)DUSP1
WikiGenes1843
SOURCE (Princeton)NM_004417
Genomic and cartography
GoldenPath (UCSC)DUSP1  -  5q35.1   chr5:172195093-172198203 -  5q35.1   [Description]    (hg19-Feb_2009)
EnsemblDUSP1 - 5q35.1 [CytoView]
Mapping of homologs : NCBIDUSP1 [Mapview]
OMIM600714   
Gene and transcription
Genbank (Entrez)AA843403 AK298047 AK298658 AK299391 AK300487
RefSeq transcript (Entrez)NM_004417
RefSeq genomic (Entrez)AC_000137 NC_000005 NC_018916 NT_023133 NW_001838954 NW_004929325
Consensus coding sequences : CCDS (NCBI)DUSP1
Cluster EST : UnigeneHs.171695 [ NCBI ]
CGAP (NCI)Hs.171695
Alternative Splicing : Fast-db (Paris)GSHG0025265
Alternative Splicing GalleryENSG00000120129
Gene ExpressionDUSP1 [ NCBI-GEO ]     DUSP1 [ SEEK ]   DUSP1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP28562 (Uniprot)
NextProtP28562  [Medical]
With graphics : InterProP28562
Splice isoforms : SwissVarP28562 (Swissvar)
Catalytic activity : Enzyme3.1.3.16 [ Enzyme-Expasy ]   3.1.3.163.1.3.16 [ IntEnz-EBI ]   3.1.3.16 [ BRENDA ]   3.1.3.16 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)RHODANESE_3 (PS50206)    TYR_PHOSPHATASE_1 (PS00383)    TYR_PHOSPHATASE_2 (PS50056)    TYR_PHOSPHATASE_DUAL (PS50054)   
Domains : Interpro (EBI)Atypical_DUSP    Dual-sp_phosphatase_cat-dom    Dual-sp_phosphatase_subgr_cat    DUSP    MKP    Rhodanese-like_dom    Tyr/Dual-sp_Pase    Tyr_Pase_AS   
Related proteins : CluSTrP28562
Domain families : Pfam (Sanger)DSPc (PF00782)    Rhodanese (PF00581)   
Domain families : Pfam (NCBI)pfam00782    pfam00581   
Domain families : Smart (EMBL)DSPc (SM00195)  RHOD (SM00450)  
DMDM Disease mutations1843
Blocks (Seattle)P28562
Human Protein AtlasENSG00000120129
Peptide AtlasP28562
HPRD02835
IPIIPI00003928   IPI00909460   IPI00942094   IPI00922849   
Protein Interaction databases
DIP (DOE-UCLA)P28562
IntAct (EBI)P28562
FunCoupENSG00000120129
BioGRIDDUSP1
InParanoidP28562
Interologous Interaction database P28562
IntegromeDBDUSP1
STRING (EMBL)DUSP1
Ontologies - Pathways
Ontology : AmiGOinactivation of MAPK activity  endoderm formation  non-membrane spanning protein tyrosine phosphatase activity  protein binding  nucleoplasm  protein dephosphorylation  response to oxidative stress  cell cycle  protein tyrosine/threonine phosphatase activity  response to light stimulus  MAP kinase tyrosine/serine/threonine phosphatase activity  response to estradiol  response to retinoic acid  cellular response to hormone stimulus  response to testosterone  intracellular signal transduction  response to hydrogen peroxide  regulation of apoptotic process  positive regulation of apoptotic process  response to glucocorticoid  negative regulation of meiotic cell cycle  response to cAMP  response to calcium ion  
Ontology : EGO-EBIinactivation of MAPK activity  endoderm formation  non-membrane spanning protein tyrosine phosphatase activity  protein binding  nucleoplasm  protein dephosphorylation  response to oxidative stress  cell cycle  protein tyrosine/threonine phosphatase activity  response to light stimulus  MAP kinase tyrosine/serine/threonine phosphatase activity  response to estradiol  response to retinoic acid  cellular response to hormone stimulus  response to testosterone  intracellular signal transduction  response to hydrogen peroxide  regulation of apoptotic process  positive regulation of apoptotic process  response to glucocorticoid  negative regulation of meiotic cell cycle  response to cAMP  response to calcium ion  
Pathways : BIOCARTATNFR2 Signaling Pathway [Genes]    Regulation of MAP Kinase Pathways Through Dual Specificity Phosphatases [Genes]    CD40L Signaling Pathway [Genes]    NFkB activation by Nontypeable Hemophilus influenzae [Genes]    Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha) [Genes]   
Pathways : KEGGMAPK signaling pathway    Serotonergic synapse   
REACTOMEDUSP1
Protein Interaction DatabaseDUSP1
Wikipedia pathwaysDUSP1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)DUSP1
SNP (GeneSNP Utah)DUSP1
SNP : HGBaseDUSP1
Genetic variants : HAPMAPDUSP1
1000_GenomesDUSP1 
ICGC programENSG00000120129 
Somatic Mutations in Cancer : COSMICDUSP1 
CONAN: Copy Number AnalysisDUSP1 
Mutations and Diseases : HGMDDUSP1
OMIM600714   
GENETestsDUSP1
Disease Genetic AssociationDUSP1
Huge Navigator DUSP1 [HugePedia]  DUSP1 [HugeCancerGEM]
Genomic VariantsDUSP1  DUSP1 [DGVbeta]
Exome VariantDUSP1
dbVarDUSP1
ClinVarDUSP1
snp3D : Map Gene to Disease1843
General knowledge
Homologs : HomoloGeneDUSP1
Homology/Alignments : Family Browser (UCSC)DUSP1
Phylogenetic Trees/Animal Genes : TreeFamDUSP1
Chemical/Protein Interactions : CTD1843
Chemical/Pharm GKB GenePA27519
Clinical trialDUSP1
Cancer Resource (Charite)ENSG00000120129
Other databases
Probes
Litterature
PubMed135 Pubmed reference(s) in Entrez
CoreMineDUSP1
iHOPDUSP1

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Contributor(s)

Written05-2012Mark Kristiansen
Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK

Citation

This paper should be referenced as such :
Kristiansen M . DUSP1 (dual specificity phosphatase 1). Atlas Genet Cytogenet Oncol Haematol. May 2012 .
URL : http://AtlasGeneticsOncology.org/Genes/DUSP1ID40371ch5q35.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/handle/2042/48225/05-2012-DUSP1ID40371ch5q35.pdf   [ Bibliographic record ]

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