Alternative titles; symbols
HGNC Approved Gene Symbol: DUSP1
Cytogenetic location: 5q35.1 Genomic coordinates (GRCh38): 5:172,768,096-172,771,195 (from NCBI)
Dual-specificity phosphatases (DUSPs) constitute a large heterogeneous subgroup of the type I cysteine-based protein-tyrosine phosphatase superfamily. DUSPs are characterized by their ability to dephosphorylate both tyrosine and serine/threonine residues. DUSP1 belongs to a class of DUSPs, designated MKPs, that dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (see 601795), JNK (see 601158), and p38 (see 600289) with specificity distinct from that of individual MKP proteins. MKPs contain a highly conserved C-terminal catalytic domain and an N-terminal Cdc25 (see 116947)-like (CH2) domain. MAPK activation cascades mediate various physiologic processes, including cellular proliferation, apoptosis, differentiation, and stress responses (summary by Patterson et al., 2009).
Keyse and Emslie (1992) isolated and characterized a DUSP1 cDNA, which they designated CL100, corresponding to an mRNA that is highly inducible by oxidative stress and heat shock in human skin cells. The cDNA was obtained by differential screening of a library made from normal human skin fibroblasts stressed for 2 hours in a solution of hydrogen peroxide. The cDNA contains an open reading frame specifying a 367-residue protein of 39.3 kD predicted molecular mass with the structural features of a nonreceptor type protein-tyrosine phosphatase. It has significant amino acid sequence similarity to a tyr/ser-protein phosphatase encoded by the late gene H1 of vaccinia virus (VH1). The purified protein encoded by the open reading frame expressed in bacteria has intrinsic phosphatase activity. Given the relationship between the levels of protein-tyrosine phosphorylation, receptor activity, cellular proliferation, and cell cycle control, Keyse and Emslie (1992) concluded that induction of this gene may play an important regulatory role in the human cellular response to environmental stress.
Using quantitative RT-PCR, Celaya et al. (2019) found that Dusp1 was expressed in inner ears of mice of all ages, with expression increasing with age.
Emslie et al. (1994) and Martell et al. (1994) mapped the DUSP1 gene by fluorescence in situ hybridization to 5q34 and 5q35, respectively.
Alessi et al. (1993) found that the phosphatase encoded by CL100 has dual specificity for tyrosine and threonine and that it specifically inactivates mitogen-activated protein kinase in vitro.
Brondello et al. (1999) determined that DUSP1, which they called MKP1, is a labile protein with a half-life of approximately 45 minutes in CCL39 hamster fibroblasts. Its degradation was attenuated by inhibitors of the ubiquitin-directed proteasome complex. MKP1 was a target in vivo and in vitro for p42MAPK (176948) or p44MAPK (601795), which phosphorylates MKP1 on 2 C-terminal serine residues, ser359 and ser364. This phosphorylation did not modify MKP1's intrinsic ability to dephosphorylate p44MAPK, but led to stabilization of the protein. Brondello et al. (1999) concluded that these results illustrated the importance of regulated protein degradation in the control of mitogenic signaling.
The MAP kinase 1,2/protein kinase C (see 176960) system is an intracellular signaling network that regulates many cellular machines, including the cell cycle machinery and autocrine/paracrine factor synthesizing machinery. Bhalla et al. (2002) used a combination of computational analysis and experiments in NIH-3T3 fibroblasts to understand the design principles of this controller network. Bhalla et al. (2002) found that the growth factor-stimulated signaling network controlled by MAPK 1,2/PKC can operate with 1 or 2 stable states. At low concentrations of MAPK phosphatase, the system exhibits bistable behavior, such that brief stimulus results in sustained MAPK activation. The MAPK-induced increase in the amounts of MAPK phosphatase eliminates the prolonged response capability and moves the network to a monostable state, in which it behaves as a proportional response system responding acutely to stimuli. Thus, the MAPK 1,2/PKC controller network is flexibly designed, and MAPK phosphatase may be critical for this flexible response.
Using whole-genome expression profiling of postmortem hippocampal tissue from 21 patients with major depressive disorder (MDD; 608516) and 18 controls, Duric et al. (2010) found significantly increased expression of MKP1 in patients with depression. There was 2.3-fold increase in the dentate gyrus and a 2.4-fold increase in the CA1 pyramidal cell layer. Similar results were found in a second cohort, with MDD patients having 31% and 16% increased MKP1 mRNA levels in the dentate gyrus and CA1 region, respectively, compared to controls. This increase was associated with downregulation of the neurotrophic factor-MAPK cascade and an inhibition of downstream ERK signaling. Studies in rats showed that chronic unpredictable stress was associated with increased Mkp1 expression in the hippocampus, and that injection of Mkp1 into hippocampus of wildtype rats induced depressive behavior. Finally, Mkp1-null rats were resistant to chronic stress-induced depressive behavior compared to controls. The findings implicated MKP1 as a key factor in the pathophysiology of MDD.
Wang et al. (2007) found that macrophages from Mkp1 -/- mice exhibited prolonged activation of p38 (MAPK14; 600289) and Jnk (MAPK8; 601158), but not Erk (see 601795), and enhanced production of Tnf (191160) and Il6 (147620) after exposure to peptidoglycan or lipoteichoic acid from gram-positive bacteria compared with wildtype macrophages. After Staphylococcus aureus challenge, Mkp1 -/- mice had higher serum Tnf, Il6, Il10 (124092), and Mip1a (CCL3; 182283) levels, accompanied by greater nitric oxide production, neutrophil infiltration, and organ dysfunction, compared with wildtype mice. Exposure to heat-killed, but not live, S. aureus resulted in lower survival rates in Mkp1 -/- mice compared with wildtype mice. Wang et al. (2007) concluded that MKP1 plays a critical role in the inflammatory response to gram-positive bacterial infection by limiting the inflammatory reaction through inactivation of JNK and p38.
Hammer et al. (2010) found that Dusp1 -/- mice exhibited increased serum, spleen, and liver Ccl4 (182284), Il10, and Il6 levels in 2 mouse models of septic peritonitis. In spite of the increased inflammatory response, bacterial clearance was impaired in Dusp1 -/- mice, which displayed increased mortality. Hammer et al. (2010) concluded that exaggerated inflammatory responses to gut bacteria in the absence of Dusp1 do not help control bacterial replication and are detrimental to the host.
Celaya et al. (2019) found that Dusp1 -/- mice exhibited premature and progressive sensorineural hearing loss, with total deafness by age 12 months. Progressive hearing loss of Dusp1 -/- mice correlated with cochlear cell loss due to apoptosis. Dusp1 deficiency generated a redox imbalance in young mice, which increased the levels of reactive oxygen species, leading to DNA damage and, eventually, apoptotic cochlear cell death. Progressive hearing loss also correlated with inflammatory dysregulation, as Dusp1 deficit increased macrophage infiltration, with an exacerbated cochlear inflammatory response in Dusp1 -/- mice. Loss of Dusp1 increased noise-induced hearing loss in mice, whereas loss of Mapk14 (600289) reduced it, suggesting that Mapk14 activation plays a central role in progression of noise-induced injury.
Alessi, D. R., Smythe, C., Keyse, S. M. The human CL100 gene encodes a tyr/thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts. Oncogene 8: 2015-2020, 1993. [PubMed: 8390041]
Bhalla, U. S., Ram, P. T., Iyengar, R. MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297: 1018-1023, 2002. [PubMed: 12169734] [Full Text: https://doi.org/10.1126/science.1068873]
Brondello, J.-M., Pouyssegur, J., McKenzie, F. R. Reduced MAP kinase phosphatase-1 degradation after p42/p44(MAPK)-dependent phosphorylation. Science 286: 2514-2517, 1999. [PubMed: 10617468] [Full Text: https://doi.org/10.1126/science.286.5449.2514]
Celaya, A. M., Sanchez-Perez, I., Bermudez-Munoz, J. M., Rodriguez-de la Rosa, L., Pintado-Bernininches, L., Perona, R., Murillo-Cuesta, S., Varela-Nieto, I. Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss. eLife 8: e39159, 2019. Note: Electronic Article. [PubMed: 30938680] [Full Text: https://doi.org/10.7554/eLife.39159]
Duric, V., Banasr, M., Licznerski, P., Schmidt, H. D., Stockmeier, C. A., Simen, A. A., Newton, S. S., Duman R. S. A negative regulator of MAP kinase causes depressive behavior. Nature Med. 16: 1328-1332, 2010. [PubMed: 20953200] [Full Text: https://doi.org/10.1038/nm.2219]
Emslie, E. A., Jones, T. A., Sheer, D., Keyse, S. M. The CL100 gene, which encodes a dual specificity (tyr/thr) MAP kinase phosphatase, is highly conserved and maps to human chromosome 5q34. Hum. Genet. 93: 513-516, 1994. [PubMed: 8168826] [Full Text: https://doi.org/10.1007/BF00202814]
Hammer, M., Echtenachter, B., Weighardt, H., Jozefowski, K., Rose-John, S., Mannel, D. N., Holzmann, B., Lang, R. Increased inflammation and lethality of Dusp1-/- mice in polymicrobial peritonitis models. Immunology 131: 395-404, 2010. [PubMed: 20561086] [Full Text: https://doi.org/10.1111/j.1365-2567.2010.03313.x]
Keyse, S. M., Emslie, E. A. Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359: 644-647, 1992. [PubMed: 1406996] [Full Text: https://doi.org/10.1038/359644a0]
Martell, K. J., Kwak, S., Hakes, D. J., Dixon, J. E., Trent, J. M. Chromosomal localization of four human VH1-like protein-tyrosine phosphatases. Genomics 22: 462-464, 1994. [PubMed: 7806236] [Full Text: https://doi.org/10.1006/geno.1994.1411]
Patterson, K. I., Brummer, T., O'Brien, P. M., Daly, R. J. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem. J. 418: 475-489, 2009. [PubMed: 19228121] [Full Text: https://doi.org/10.1042/bj20082234]
Wang, X., Meng, X., Kuhlman, J. R., Nelin, L. D., Nicol, K. K., English, B. K., Liu, Y. Knockout of Mkp-1 enhances the host inflammatory responses to Gram-positive bacteria. J. Immun. 178: 5312-5320, 2007. [PubMed: 17404316] [Full Text: https://doi.org/10.4049/jimmunol.178.8.5312]