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Chen, Hsueh-Fen, Huai-Chia Chuang i Tse-Hua Tan. "Regulation of Dual-Specificity Phosphatase (DUSP) Ubiquitination and Protein Stability". International Journal of Molecular Sciences 20, nr 11 (30.05.2019): 2668. http://dx.doi.org/10.3390/ijms20112668.
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Mitogen-activated protein kinases (MAPKs) are key regulators of signal transduction and cell responses. Abnormalities in MAPKs are associated with multiple diseases. Dual-specificity phosphatases (DUSPs) dephosphorylate many key signaling molecules, including MAPKs, leading to the regulation of duration, magnitude, or spatiotemporal profiles of MAPK activities. Hence, DUSPs need to be properly controlled. Protein post-translational modifications, such as ubiquitination, phosphorylation, methylation, and acetylation, play important roles in the regulation of protein stability and activity. Ubiquitination is critical for controlling protein degradation, activation, and interaction. For DUSPs, ubiquitination induces degradation of eight DUSPs, namely, DUSP1, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, and DUSP16. In addition, protein stability of DUSP2 and DUSP10 is enhanced by phosphorylation. Methylation-induced ubiquitination of DUSP14 stimulates its phosphatase activity. In this review, we summarize the knowledge of the regulation of DUSP stability and ubiquitination through post-translational modifications.
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Chuang i Tan. "MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus". Cells 8, nr 11 (13.11.2019): 1433. http://dx.doi.org/10.3390/cells8111433.
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T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt–AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.
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Lim, S., J. A. Green, H. Wong, M. E. VanderBurg i T. Crook. "DUSP7 and DUSP8 promoter hypermethylations: Predictors of clinical outcomes in advanced epithelial ovarian carcinoma". Journal of Clinical Oncology 25, nr 18_suppl (20.06.2007): 5501. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.5501.
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5501 Background: The Dual specificity phosphatases (DUSPs) are a subclass of the protein tyrosine phosphatase (PTP) gene family which appears to be selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues within the mitogen-activated protein kinases (MAPKs) leading to inactivation. MAPK activation is a downstream target of several oncogenes and may give rise to oncogenic transformation, and hence DUSPs are potential tumor suppressor genes. The aim of this study was to investigate if DUSPs are subject to methylation-dependent silencing in epithelial ovarian cancer. Methods: In this study, promoter methylation and gene expression of the DUSPs genes (DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8 and DUSP10) were investigated in 9 ovarian cancer cell lines and in 74 primary epithelial ovarian tumors (Stage III/IV), using methylation specific PCR (MSP) and Reverse- transcription PCR (RT-PCR). The 74 clinical samples were retrospectively retrieved from a large Phase III RCT (the EORTC 55931/NCIC OV10) with clinical follow-up in excess of 6.5 years. Results: Ovarian Cancer Cell lines: Aberrant CpG methylation detected in DUSP1, DUSP2, DUSP4, DUSP6, DUSP7 and DUSP8. DUSP7 promoter methylation was associated with downregulation of mRNA expression. Primary Ovarian Tumors: Methylation of DUSP1, DUSP2, DUSP7 and DUSP8 was observed in 15–38% of the primary tumors. DUSP7 methylation is a predictor of adverse PFS in both univariate (median PFS 10.6 m versus 13.3m, p=0.002) and multivariate (Cox Regression HR 2.76, p<0.001) analyses, and is associated with a trend for poorer OS (22.1 m versus 29.3 m, p=0.07). In contrast, DUSP8 methylation is an independent predictor of favorable PFS (median 23.7m versus 11.5m; Cox Regression HR 0.30, p=0.006) and OS (HR 0.31, p=0.013). 5-year OS for DUSP8 methylated patients was 58.3% compared with 16.1% for DUSP8 unmethylated (HR 0.277, p=0.005). Conclusion: This is the first report of DUSP methylation in epithelial ovarian cancer. The study suggests that methylation-dependent transcriptional silencing of DUSP7 in advanced epithelial ovarian cancer may represent an independent predictor of adverse PFS. DUSP8 methylation, on the other hand, is a favorable clinical outcome marker. No significant financial relationships to disclose.
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Bermudez, O., G. Pagès i C. Gimond. "The dual-specificity MAP kinase phosphatases: critical roles in development and cancer". American Journal of Physiology-Cell Physiology 299, nr 2 (sierpień 2010): C189—C202. http://dx.doi.org/10.1152/ajpcell.00347.2009.
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Intracellular signaling by mitogen-activated protein (MAP) kinases (MAPK) is involved in many cellular responses and in the regulation of various physiological and pathological conditions. Tight control of the localization and duration of extracellular-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), or p38 MAPK activity is thus a fundamental aspect of cell biology. Several members of the dual-specificity phosphatase (DUSPs) family are able to dephosphorylate MAPK isoforms with different specificity, cellular, and tissue localization. Understanding how these phosphatases are themselves regulated during development or in physiological and pathological conditions is therefore fundamental. Over the years, gene deletion and knockdown studies have completed initial in vitro studies and shed a new light on the global and specific roles of DUSPs in vivo. Whereas DUSP1, DUSP2, and DUSP10 appear as crucial players in the regulation of immune responses, other members of the family, like the ERK-specific DUSP6, were shown to play a major role in development. Recent findings on the involvement of DUSPs in cancer progression and resistance will also be discussed.
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Jeong, Dae-Gwin, Song-Yi Kim, Jeong-Hun Yun i Jae-Hoon Kim. "Characterization of a Dual-Specificity Protein Phosphatase, Human DUSP28". Journal of Life Science 21, nr 1 (30.01.2011): 31–35. http://dx.doi.org/10.5352/jls.2011.21.1.31.
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Hahn, Cynthia K., Rachel J. West, Elizabeth R. Macari, Emily K. Schaeffer i Christopher H. Lowrey. "Dual-Specificity Phosphatases (DUSPs) Are Potential Targets for Pharmacologic Induction of Fetal Hemoglobin". Blood 116, nr 21 (19.11.2010): 2075. http://dx.doi.org/10.1182/blood.v116.21.2075.2075.
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Abstract Abstract 2075 Morbidities of sickle cell anemia and β-thalassemia can be alleviated by increased fetal hemoglobin (HbF) production. However, currently available HbF inducing agents, such as HU, butyrate, and DNA methyltransferase inhibitors are not ideal due to suppression of hematopoiesis and other short and long-term side effects. Our goal is to identify novel HbF induction strategies that have the safety, efficacy and ease of use to make them applicable to most hemoglobinopathy patients. Recently, we proposed that most inducing agents increase γ-globin gene expression through activation of cell stress signaling pathways, including the p38 MAPK pathway (Mabaera et al, Exp Hematol. 2008). Evidence supporting the involvement of p38 signaling in HbF induction includes publications from multiple groups showing that γ-globin mRNA induction by several agents activates p38 signaling and can be suppressed by inhibitors of p38. Our lab has shown that physical stresses such as hyperosmotic shock, UV and X-ray irradiation, and heat shock are capable of activating p38 and inducing γ-globin mRNA expression in erythroid cells that is blocked by SB203580, a p38 inhibitor. If our model is correct, strategies that increase p38 signaling without cellular stress could be therapeutically beneficial. One possible approach is inhibition of the dual-specificity phosphatases (DUSPs) that are induced by MAPK signaling and then feedback to dephosphorylate activated MAPKs including p38. If this model is correct, suppression of DUSP activity could increase basal levels of p38 signaling without stress. Regulation of specific MAPK pathways by different DUSPs is cell-type and stress-type dependent. To determine which DUSPs are likely to be involved in p38 signaling in erythroid cells, we first used RT-PCR to determine which of ten DUSPs that are known to modulate MAPK signaling (DUSPs 1, 2, 4, 5, 6, 7, 8, 9, 10, and 16) are expressed in human erythroid progenitors and K562 cells. All ten DUSPs were expressed in both cell types. Next, we determined the effects of hemin (10 and 20μM) and Na butyrate (1 and 2mM), two known inducers of HbF and p38 MAPK signaling, on mRNA levels of the ten DUSP genes in K562 cells. γ-globin mRNA was induced by both drugs at these doses. DUSP gene expression was assessed during a short time course ranging from 5 minutes to 5 hours and a longer time course from 24 to 72 hours. At early time points, DUSP5 expression was induced up to 4-fold with both drugs when compared to untreated controls. DUSP5 continued to have the greatest level of induction at later time points (up to 8-fold) while DUSP4 and DUSP6 reached maximum induction (up to 4-fold) at 72 hours. Treatment of K562 cells with a small molecule inhibitor of DUSP1 and DUSP6, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-iden-1-one (BCI, gift of Dr. John Lazo) at 1μM increased γ-globin mRNA levels 5-fold, similar to levels seen with hemin and butyrate, and increased p38 phosphorylation by western blotting. Together, these data suggest that DUSPs may be a molecular target for the development of novel HbF inducing agents. Disclosures: No relevant conflicts of interest to declare.
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De Roock, W., M. Janssens, B. Biesmans, B. Jacobs, J. De Schutter, S. Fieuws, E. Van Cutsem i S. Tejpar. "DUSPs as markers of MEK/Erk activation in primary colorectal cancer". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): 4064. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4064.
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4064 Background: DUSPs dephosphorylate P-MAPK and are activated as a negative feedback loop upon RTK signaling. Higher expression of DUSP 4 & 6 is also found in cells with constitutive Erk activation like KRAS mutant (MUT) cells (Bild et al. Nature 2005). We correlated DUSP1, 4, 6 (isoforms a & b) & 8 mRNA expression level in FFPE primary colorectal cancer (CRC) of 186 chemorefractory patients treated with cetuximab (CTX) with KRAS MUT state and progression-free survival (PFS) and overall survival (OS). Methods: KRAS codon 12,13, 61&146, BRAF V600E and NRAS codon 12&13 MUT were analyzed with the Sequenom MALDI TOF MassArray system. The DUSPs and 3 housekeeping genes were quantified by qRT-PCR. TwoStep cluster analysis was performed. PFS and OS were estimated by the Kaplan-Meier method. Results: KRAS MUT was associated with increased DUSP4 (MWU;p=.0006) & 6a (p=.0067). DUSP6a dephosphorylates P-Erk, DUSP4 also dephosphorylates P-JNK & P-p38. DUSP1 & 8 primarily dephosphorylate P-JNK & P-p38 and were not associated with KRAS MUT. KRAS MUT clustered into 3 groups according to DUSP4 expression: 32 high, 38 median & 13 low (t- test;p<.0001). The low MUT expression was comparable to wild-type (WT) expression. KRAS WT clustered into 2 groups: 69 low & 24 high DUSP4 (ANOVA;p<.0001). 7/24 of high expressors were found to have a BRAF or NRAS MUT. The 32 MUT high expressors had a longer median PFS (log-rank;p=.015) and OS (p=.065) after CTX. The 17 KRAS/BRAF/NRAS WT high expressors had a shorter median OS (p=.026), but not PFS (p=.745). Conclusions: There is a significantly higher DUSP4 & 6a mRNA expression in the KRAS MUT compared to WT primary CRC. However, this is not a black and white observation. In the KRAS MUT there are 3 distinct clusters of DUSP4 expression. The high expressors (= supposed attenuated Erk signaling) have a longer PFS and OS after CTX. Adaptation to constitutive KRAS signaling with differential levels of MEK/Erk activation needs to be further investigated and will be of help in selecting patients for therapy with MEK inhibitors. It suggests not all KRAS MUT will be good candidates for MEK inhibitors. In the cluster of high DUSP4 expressing KRAS WT 30% are BRAF or NRAS MUT. This suggests DUSP expression of FFPE samples could be a more sensitive marker of MEK/Erk activation and resistance to EGFR inhibitors than KRAS MUT analysis alone. [Table: see text]
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Thompson, Elliott M., i Andrew W. Stoker. "A Review of DUSP26: Structure, Regulation and Relevance in Human Disease". International Journal of Molecular Sciences 22, nr 2 (14.01.2021): 776. http://dx.doi.org/10.3390/ijms22020776.
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Dual specificity phosphatases (DUSPs) play a crucial role in the regulation of intracellular signalling pathways, which in turn influence a broad range of physiological processes. DUSP malfunction is increasingly observed in a broad range of human diseases due to deregulation of key pathways, most notably the MAP kinase (MAPK) cascades. Dual specificity phosphatase 26 (DUSP26) is an atypical DUSP with a range of physiological substrates including the MAPKs. The residues that govern DUSP26 substrate specificity are yet to be determined; however, recent evidence suggests that interactions with a binding partner may be required for DUSP26 catalytic activity. DUSP26 is heavily implicated in cancer where, akin to other DUSPs, it displays both tumour-suppressive and -promoting properties, depending on the context. Here we review DUSP26 by evaluating its transcriptional patterns, protein crystallographic structure and substrate binding, as well as its physiological role(s) and binding partners, its role in human disease and the development of DUSP26 inhibitors.
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WANG, DONG, SHENG HAN, RUI PENG, CHENYU JIAO, XING WANG, ZEGUANG HAN i XIANGCHENG LI. "DUSP28 contributes to human hepatocellular carcinoma via regulation of the p38 MAPK signaling". International Journal of Oncology 45, nr 6 (16.09.2014): 2596–604. http://dx.doi.org/10.3892/ijo.2014.2653.
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Cooper, Lisa M., Rita C. West, Caleb S. Hayes i David S. Waddell. "Dual-specificity phosphatase 29 is induced during neurogenic skeletal muscle atrophy and attenuates glucocorticoid receptor activity in muscle cell culture". American Journal of Physiology-Cell Physiology 319, nr 2 (1.08.2020): C441—C454. http://dx.doi.org/10.1152/ajpcell.00200.2020.
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Skeletal muscle atrophy is caused by a decrease in muscle size and strength and results from a range of physiological conditions, including denervation, immobilization, corticosteroid exposure and aging. Newly named dual-specificity phosphatase 29 ( Dusp29) has been identified as a novel neurogenic atrophy-induced gene in skeletal muscle. Quantitative PCR analysis revealed that Dusp29 expression is significantly higher in differentiated myotubes compared with proliferating myoblasts. To determine how Dusp29 is transcriptionally regulated in skeletal muscle, fragments of the promoter region of Dusp29 were cloned, fused to a reporter gene, and found to be highly inducible in response to ectopic expression of the myogenic regulatory factors (MRF), MyoD and myogenin. Furthermore, site-directed mutagenesis of conserved E-box elements within the proximal promoter of Dusp29 rendered a Dusp29 reporter gene unresponsive to MRF overexpression. Dusp29, an atypical Dusp also known as Dupd1/Dusp27, was found to attenuate the ERK1/2 branch of the MAP kinase signaling pathway in muscle cells and inhibit muscle cell differentiation when ectopically expressed in proliferating myoblasts. Interestingly, Dusp29 was also found to destabilize AMPK protein while simultaneously enriching the phosphorylated pool of AMPK in muscle cells. Additionally, Dusp29 overexpression resulted in a significant increase in the glucocorticoid receptor (GR) protein and elevation in GR phosphorylation. Finally, Dusp29 was found to significantly impair the ability of the glucocorticoid receptor to function as a transcriptional activator in muscle cells treated with dexamethasone. Identifying and characterizing the function of Dusp29 in muscle provides novel insights into the molecular and cellular mechanisms for skeletal muscle atrophy.
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Zhang, Yongliang, Huipeng Jiao i Sharmy J. James. "DUSP4 regulates STING- and RIG-I-mediated signalling in response to virus infection". Journal of Immunology 200, nr 1_Supplement (1.05.2018): 169.21. http://dx.doi.org/10.4049/jimmunol.200.supp.169.21.
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Abstract MAPK phosphatase (MKPs), also known as dual-specificity phosphatases (DUSPs), are cysteine-based protein tyrosine phosphatases that dephosphorylate phosphotyrosine, phosphothreonine, and phosphoserine residues in their substrates. They are originally identified as the major negative regulators of MAP kinases (MAPKs). Our recent study on DUSP10/MKP5 demonstrated that this molecule plays an important role in immune response to virus infection via dephosphorylating IRF3. DUSP4/MKP2 is another DUSP/MKP family member whose function in immune response to virus infection is unclear. This study aims to elucidate the regulatory function of DUSP4 in STING- and RIG-I-mediated signaling and in innate immune response to virus infection. We found that this protein is constitutively expressed in immune cells such as macrophages and its expression is increased in response to the activation of RIG-I and STING as well as virus infection including influenza and HSV. Studies using cells and mice deficient in DUSP4/MKP2 demonstrate that this molecule inhibits STING- and RIG-I-mediated signaling, thereby inhibiting the expression of proinflammatory cytokines including IL-6 and TNFa as well as type I interferon such as IFNb. Furthermore, DUSP4 deficient mice developed less severe diseases upon influenza and HSV infection, but more severe disease upon malaria parasite infection. Our studies demonstrate a novel function of DUSP4 in immune response to microbial infection and may be further explored for therapeutic purposes.
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Cañas, José A., Marcela Valverde-Monge, José M. Rodrigo-Muñoz, Beatriz Sastre, Marta Gil-Martínez, Raquel García-Latorre, Manuel J. Rial i in. "Serum microRNAs as Tool to Predict Early Response to Benralizumab in Severe Eosinophilic Asthma". Journal of Personalized Medicine 11, nr 2 (28.01.2021): 76. http://dx.doi.org/10.3390/jpm11020076.
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Severe eosinophilic asthma poses a serious health and economic problem, so new therapy approaches have been developed to control it, including biological drugs such as benralizumab, which is a monoclonal antibody that binds to IL-5 receptor alpha subunit and depletes peripheral blood eosinophils rapidly. Biomarkers that predict the response to this drug are needed so that microRNAs (miRNAs) can be useful tools. This study was performed with fifteen severe eosinophilic asthmatic patients treated with benralizumab, and serum miRNAs were evaluated before and after treatment by semi-quantitative PCR (qPCR). Patients showed a clinical improvement after benralizumab administration. Additionally, deregulation of miR-1246, miR-5100 and miR-338-3p was observed in severe asthmatic patients after eight weeks of therapy, and a correlation was found between miR-1246 and eosinophil counts, including a number of exacerbations per year in these severe asthmatics. In silico pathway analysis revealed that these three miRNAs are regulators of the MAPK signaling pathway, regulating target genes implicated in asthma such as NFKB2, NFATC3, DUSP1, DUSP2, DUSP5 and DUSP16. In this study, we observed an altered expression of miR-1246, miR-5100 and miR-338-3p after eight weeks of benralizumab administration, which could be used as early response markers.
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Kung, Jennifer E., i Jawahar Sudhamsu. "Abstract A023: Structural basis for regulation of MAPK signaling by DUSP5 and DUSP6". Molecular Cancer Research 21, nr 5_Supplement (1.05.2023): A023. http://dx.doi.org/10.1158/1557-3125.ras23-a023.
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Abstract The Ras/mitogen-activated protein kinase (MAPK) cascade plays an essential role in several critical cellular processes, such as cell growth and proliferation, and hyperactivation of this pathway is frequently observed in cancer. DUSP5 and DUSP6 are dual specificity phosphatases (capable of dephosphorylating phospho-tyrosines as well as phospho-serines/threonines) that act as key regulators of MAPK signaling that inactivate ERK by dephosphorylating its activation loop and sequestering ERK in an inactive state. DUSP5 and DUSP6 have been reported to function as tumor suppressors in some Ras-driven cancers, including skin cancer and pancreatic cancer, while promoting tumorigenesis in other contexts, such as thyroid cancer or glioblastoma. Despite the importance of these phosphatases in modulating ERK signaling, the structural basis for their interaction with ERK and their dual specificity remain poorly understood. It has also been reported that ERK binding allosterically activates DUSP6, but not DUSP5, and the mechanism underlying this is unclear. While structures of individual domains of these proteins have been solved, there are no structures of full-length DUSP5 or DUSP6, or of an ERK/DUSP complex. To gain insight into the molecular determinants of ERK dephosphorylation by these phosphatases, we have purified full-length DUSP5 and DUSP6, as well as the phosphatase domains of both proteins. We have also generated full-length phosphorylated ERK2 (pERK2). Through in vitro dephosphorylation assays, we have observed that full-length DUSP5 and DUSP6 dephosphorylate ERK2 much more rapidly than the isolated phosphatase domains, indicating an essential role for their N-terminal regulatory domains in this process. Using biolayer interferometry, we show that catalytically inactive mutants of full-length DUSP5 and DUSP6 bind very tightly to pERK2 with low nanomolar affinity. We have reconstituted complexes of pERK2 bound to catalytically inactive full-length DUSP5 or DUSP6, and we are pursuing structures of these complexes using x-ray crystallography and cryo-electron microscopy. These studies will improve our understanding of the regulation of ERK and its phosphatases DUSP5 and DUSP6 and shed light on the similarities and differences between these complexes. These structures could also potentially reveal the structural features underlying the dual specificity of DUSP5 and DUSP6. Citation Format: Jennifer E. Kung, Jawahar Sudhamsu. Structural basis for regulation of MAPK signaling by DUSP5 and DUSP6 [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A023.
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Bellou, Sofia, Mark A. Hink, Eleni Bagli, Ekaterini Panopoulou, Philippe I. H. Bastiaens, Carol Murphy i Theodore Fotsis. "VEGF autoregulates its proliferative and migratory ERK1/2 and p38 cascades by enhancing the expression of DUSP1 and DUSP5 phosphatases in endothelial cells". American Journal of Physiology-Cell Physiology 297, nr 6 (grudzień 2009): C1477—C1489. http://dx.doi.org/10.1152/ajpcell.00058.2009.
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Vascular endothelial growth factor (VEGF) is a key angiogenic factor that regulates proliferation and migration of endothelial cells via phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2) and p38, respectively. Here, we demonstrate that VEGF strongly induces the transcription of two dual-specificity phosphatase (DUSP) genes DUSP1 and DUSP5 in endothelial cells. Using fluorescence microscopy, fluorescence lifetime imaging (FLIM), and fluorescence cross-correlation spectroscopy (FCCS), we found that DUSP1/mitogen-activated protein kinases phosphatase-1 (MKP-1) was localized in both the nucleus and cytoplasm of endothelial cells, where it existed in complex with p38 (effective dissociation constant, KDeff, values of 294 and 197 nM, respectively), whereas DUSP5 was localized in the nucleus of endothelial cells in complex with ERK1/2 ( KDeff 345 nM). VEGF administration affected differentially the KDeff values of the DUSP1/p38 and DUSP5/ERK1/2 complexes. Gain-of-function and lack-of-function approaches revealed that DUSP1/MKP-1 dephosphorylates primarily VEGF-phosphorylated p38, thereby inhibiting endothelial cell migration, whereas DUSP5 dephosphorylates VEGF-phosphorylated ERK1/2 inhibiting proliferation of endothelial cells. Moreover, DUSP5 exhibited considerable nuclear anchoring activity on ERK1/2 in the nucleus, thereby diminishing ERK1/2 export to the cytoplasm decreasing its further availability for activation.
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Li, Wei-ming, Yi-fan Zhao, Guo-fu Zhu, Wen-hui Peng, Meng-yun Zhu, Xue-jing Yu, Wei Chen, Da-chun Xu i Ya-wei Xu. "Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload". Clinical Science 131, nr 2 (23.12.2016): 141–54. http://dx.doi.org/10.1042/cs20160664.
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Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1/2 activity but neither ERK1/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in vitro and in vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy.
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JI, WENXIAO, Wen G. Jiang, Lin Ye i Tracey A. Martin. "Abstract P2-16-09: Dual Specific Phosphatase-7 (DUSP7/PYST2) and its role in regulating vascular endothelial functions". Cancer Research 83, nr 5_Supplement (1.03.2023): P2–16–09—P2–16–09. http://dx.doi.org/10.1158/1538-7445.sabcs22-p2-16-09.
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Abstract Dual Specific Phosphatase-7 (DUSP7/PYST2) and its role in regulating vascular endothelial functions Wenxiao Ji, Wen G. Jiang, Lin Ye, Tracey A. Martin CCMRC, Cardiff University School of Medicine, Cardiff, Wales, UK Introduction. Dual specific phosphatases (DUSPs) are a large family of enzyme able to trigger tyrosine phosphorylation, and phosphorylation of serine and/or threonine. This feature of a dual phosphorylation pattern by DUSPs, renders them with diverse roles in cells, from cytoskeletal regulation of cell migration, regulation of multiple kinases in cell signalling, to regulation of proteins such as microtubules and cell growth. We have investigated DUSP family members, in particular DUSP-7 (otherwise known as PYST2), identified from our studies as being one of prominent DUSPs found to be highly aberrant in certain cancer types including gastric cancer and pancreatic cancer. In breast cancer cells, DUSP7 has been reported as a potential factor linked to drug sensitivity. The role played by DUSP7 in vascular endothelial cells has been poorly studied. Here, we present our findings on the role of DUSP-7 in the regulation of biological functions of vascular endothelial cells. Methods. Human vascular endothelial cells were used in the present study. Cell sub-models were created by knock down of DUSP7. The cells were evaluated for their biological response to loss of DUSP7, including proliferation, migration, matrix adhesion and response to downstream signalling. DUSP7 responses to various exogenous factors were also evaluated by a protein kinase platform. Results. Knock down of DUSP7 in human endothelial cells rendered them manifesting significantly reduced matrix adhesiveness (p< 0.05) and most strikingly, reduced cellular migration (P< 0.0001, control versus DUSP7 knock down). Interestingly, there was little change with the rate of cell growth. When cells were tested by inhibiting a tight junctional molecule, HAVcR1, the endothelial cells responded with markedly reduced DUSP7 (reduction of 46%). Likewise, the cells were also exhibited reduced levels of DUSP7 after being challenged by exogenous metastasis related Kisspeptin, indicating that DUSP7 may participated the wide network of signalling and functional regulations shared with the tight junction regulator HAVcR1 and possibly utilising Mitogen-activated protein kinase 3 (MAPK3 or Extracellular signal regulated kinase-1). Conclusion. Dual specific phosphatase-7 has an important role to play in vascular endothelial cells, primarily on cell matrix adhesion and cellular migration. A possible route of regulation is by targeting the extracellular signalling network. Citation Format: WENXIAO JI, Wen G. Jiang, Lin Ye, Tracey A. Martin. Dual Specific Phosphatase-7 (DUSP7/PYST2) and its role in regulating vascular endothelial functions [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-09.
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Wu, Fan, Robert D. McCuaig, Christopher R. Sutton, Abel H. Y. Tan, Yoshni Jeelall, Elaine G. Bean, Jin Dai i in. "Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer". International Journal of Molecular Sciences 20, nr 12 (24.06.2019): 3080. http://dx.doi.org/10.3390/ijms20123080.
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DUSP6 is a dual-specificity phosphatase (DUSP) involved in breast cancer progression, recurrence, and metastasis. DUSP6 is predominantly cytoplasmic in HER2+ primary breast cancer cells, but the expression and subcellular localization of DUSPs, especially DUSP6, in HER2-positive circulating tumor cells (CTCs) is unknown. Here we used the DEPArray system to identify and isolate CTCs from metastatic triple negative breast cancer (TNBC) patients and performed single-cell NanoString analysis to quantify cancer pathway gene expression in HER2-positive and HER2-negative CTC populations. All TNBC patients contained HER2-positive CTCs. HER2-positive CTCs were associated with increased ERK1/ERK2 expression, which are direct DUSP6 targets. DUSP6 protein expression was predominantly nuclear in breast CTCs and the brain metastases but not pleura or lung metastases of TNBC patients. Therefore, nuclear DUSP6 may play a role in the association with cancer spreading in TNBC patients, including brain metastasis.
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Qiu, Tao, Tianyu Wang, Jiangqiao Zhou, Zhongbao Chen, Jilin Zou, Long Zhang i Xiaoxiong Ma. "DUSP12 protects against hepatic ischemia–reperfusion injury dependent on ASK1-JNK/p38 pathway in vitro and in vivo". Clinical Science 134, nr 17 (wrzesień 2020): 2279–94. http://dx.doi.org/10.1042/cs20191272.
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Abstract Hepatic ischemia–reperfusion (I/R) injury is an important risk factor resulting in liver failure during liver surgery. However, there is still lack of effective therapeutic methods to treat hepatic I/R injury. DUSP12 is a member of the dual specific phosphatase (DUSP) family. Some DUSPs have been identified as being involved in the regulation of hepatic I/R injury. However, the role of DUSP12 during hepatic I/R injury is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in a hepatic I/R injury mouse model in vivo and in hypoxia/reoxygenation (H/R) model in vitro. Using hepatocyte-specific DUSP12 knockout mice and DUSP12 transgenic mice, we demonstrated that DUSP12 apparently relieved I/R-induced liver injury. Moreover, DUSP12 inhibited hepatic inflammatory responses and alleviated apoptosis both in vitro and in vivo. Furthermore, we demonstrated that JNK and p38 activity, but not ERK1/2, was increased in the DUSP12-deficient mice and decreased in the DUSP12 transgenic mice under I/R condition. ASK1 was required for DUSP12 function in hepatic I/R injury and inhibition of ASK1 prevented inflammation and apoptosis in DUSP12-deficient hepatocytes and mice. In conclusion, DUSP12 protects against hepatic I/R injury and related inflammation and apoptosis. This regulatory role of DUSP12 is primarily through ASK1-JNK/p38 signaling pathway. Taken together, DUSP12 could be a potential therapeutic target for hepatic I/R injury.
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Lee, Jungwhoi, Jungsul Lee i Jae-Hoon Kim. "Scattered DUSP28 is a novel biomarker responsible for aggravating malignancy via the autocrine and paracrine signaling in metastatic pancreatic cancer". Cancer Letters 456 (sierpień 2019): 1–12. http://dx.doi.org/10.1016/j.canlet.2019.03.006.
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Lee, Jungwhoi, Jungsul Lee, Jeong-Hun Yun, Dae Gwin Jeong i Jae Hoon Kim. "DUSP28 links regulation of Mucin 5B and Mucin 16 to migration and survival of AsPC-1 human pancreatic cancer cells". Tumor Biology 37, nr 9 (26.05.2016): 12193–202. http://dx.doi.org/10.1007/s13277-016-5079-x.
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Smith, Anna, Cathy Price, Martin Cullen, Marco Muda, Andrea King, Bradford Ozanne, Steve Arkinstall i Alan Ashworth. "Chromosomal Localization of Three Human Dual Specificity Phosphatase Genes (DUSP4, DUSP6, and DUSP7)". Genomics 42, nr 3 (czerwiec 1997): 524–27. http://dx.doi.org/10.1006/geno.1997.4756.
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Armstrong, Stephen Paul, Christopher James Caunt i Craig Alexander McArdle. "Gonadotropin-Releasing Hormone and Protein Kinase C Signaling to ERK: Spatiotemporal Regulation of ERK by Docking Domains and Dual-Specificity Phosphatases". Molecular Endocrinology 23, nr 4 (1.04.2009): 510–19. http://dx.doi.org/10.1210/me.2008-0333.
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Abstract Activated ERK translocates to the nucleus to regulate transcription. Spatiotemporal aspects of this response dictate biological consequences and are influenced by dual-specificity phosphatases (DUSPs) that can scaffold and dephosphorylate ERK. In HeLa cells, GnRH causes transient and protein kinase C (PKC)-dependent ERK activation, but termination mechanisms are unknown. We now explore DUSP roles using short inhibitory RNA to knock down endogenous ERK, adenoviruses to express GnRH receptors and add-back ERK2-GFP, and automated microscopy to monitor ERK location and activation. GnRH caused rapid and transient increases in dual phosphorylated ERK2 (ppERK2) and nuclear to cytoplasmic ERK2-green fluorescent protein (GFP) ratio, whereas responses to a PKC-activating phorbol ester were more sustained. In cells expressing D319N ERK2-GFP (D319N mutation impairs docking-domain-dependent binding to DUSPs), GnRH caused more sustained increases in ppERK2 and nuclear to cytoplasmic ERK2-GFP ratio and also had more pronounced effects on Egr-1 luciferase (a transcriptional reporter for ERK activation). Cycloheximide caused more sustained effects of GnRH and phorbol ester on ppERK, suggesting termination by nuclear-inducible DUSPs. GnRH also increased expression of nuclear-inducible DUSP1 and -4, but their knockdown did not alter GnRH-mediated ERK signaling. Screening a short inhibitory RNA library targeting 16 DUSPs (nuclear-inducible DUSPs, cytoplasmic ERK MAPK phosphatases, c-Jun N-terminal kinase/p38 MAPK phosphatases, and atypical DUSPs) revealed GnRH effects to be influenced by DUSPs 5, 9, 10, 16, and 3 (i.e. by each DUSP class). Thus, GnRH-mediated ERK responses (like PKC-mediated ERK responses) are dependent on protein neosynthesis and docking-domain-dependent binding, but for GnRH activation (unlike PKC activation), this does not reflect dependence on nuclear-inducible DUSPs. Termination of these GnRH effects is apparently dependent upon a preexisting rapid turnover protein.
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Chen, Hui, Chunting Zhang, Qianmei Zhou, Yanan Guo, Zhigang Ren i Zujiang Yu. "Integrated Bioinformatic Analysis Identifies TIPIN as a Prognostic Biomarker in Hepatocellular Carcinoma". Disease Markers 2022 (17.01.2022): 1–15. http://dx.doi.org/10.1155/2022/5764592.
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Background. Gene expression and DNA methylation analyses have long been used to identify cancer markers. However, a combination analysis of the gene expression and DNA methylation has yet to be performed to identify potential biomarkers of hepatocellular carcinoma (HCC). Methods. By matching gene expression profiles and promoter methylation data in The Cancer Genome Atlas (TCGA), genes with discrepant expression as well as genes with differential promoter methylation were identified. High-expression genes with low promoter methylation were defined as epigenetically induced (EI), while low-expression genes with high promoter methylation were defined as epigenetically suppressed (ES). The human protein interaction network was further integrated to construct the EI/ES gene interaction network, and the key genes in the subnet were identified as potential HCC biomarkers. The expression differences and prognostic values were verified in TCGA and Gene Expression Omnibus (GEO) databases, as well as with tissue chip technology. Results. Four key genes were identified: TIPIN, RBM15B, DUSP28, and TRIM31, which demonstrated the differential gene expression and prognostic value in TCGA and GEO databases. Tissue microarray analysis (TMA) revealed that TIPIN levels were altered in HCC. The upregulated TIPIN expression was associated with worse overall survival. Univariate and multivariate analyses showed that the TIPIN expression was an independent predictor of HCC. Conclusion. TIPIN might be a potential novel prognostic biomarker for HCC.
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Lu, Yi, i Yongliang Zhang. "Protective function of DUSP4 in DSS-induced colitis". Journal of Immunology 204, nr 1_Supplement (1.05.2020): 76.15. http://dx.doi.org/10.4049/jimmunol.204.supp.76.15.
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Abstract Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract. The mitogen-activated protein kinase (MAPK) signalling, an evolutionary conserved cell signalling pathway, is associated with IBD. MAPKs comprises ERK, P38, and JNK, which are activated by upstream MKKs and MKKKs, and are inactivated by dual specificity phosphatases (DUSPs). DUSP4 (MPK2) is a member of DUSP protein family and was found to be involved in various physiological processes. However the role of DUSP4 in IBD is yet to be examined. In this study, we utilized DSS-induced colitis mouse model to investigate the function of DUSP4 in this disease. We found that DUSP4 knockout (KO) mice were more susceptible to DSS-induced colitis, which was demonstrated by more weight loss and higher histological score than wild-type (WT) mice. Consistently, expression of inflammatory cytokines, including IL-6, TNF-α, IL-17A, and CXCL-1, was enhanced in both proximal and distal colon of DUSP4 KO mice compared to WT mice. Moreover, excessive CD8+ and CD4+ cells, especially IL-17A-expressing CD4+ T cells, were identified in the mesenteric lymph node (mLN) of the KO mice. Together, these results demonstrated that deficiency of DUSP4 resulted in increased inflammation in the gut in response to DSS.
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Pedersen, Martin Bjerregård, Thomas Relander, Grete Fossum Lauritzsen, Fredrik Ellin, Sirpa Leppä, Susanna Mannisto, Esa Jantunen i in. "The Impact of Upfront Autologous Transplant on the Survival of Adult Patients with ALCL and PTCL-NOS According to Their ALK, DUSP22 and TP63 Gene Rearrangement Status - a Joined Nordic Lymphoma Group and Mayo Clinic Analysis". Blood 130, Suppl_1 (7.12.2017): 822. http://dx.doi.org/10.1182/blood.v130.suppl_1.822.822.
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Abstract Introduction: Recent results from two independent patient series have shown that chromosomal rearrangements of DUSP22 (DUSP22r+) and TP63 (TP63r+) can predict outcome in ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) with morphologic features resembling ALK-ALCL (Parilla-Castellar E, Blood 2014; Pedersen MB, Blood 2017). While DUSP22r+ is predictive for excellent survival similar to that of ALK+ALCL after CHOP/CHOP-like therapy, the rarely occurring TP63r+ is associated with an aggressive clinical behavior and poor outcome. The largest subgroup, i.e. patients with neither ALK nor DUSP22 nor TP63 rearrangements (triple negative), show a 5 year (yr) overall survival (OS) intermediate between that of ALK-/DUSP22r+ and ALK-/TP63r+ patients. The aim of the present study was to assess the impact of upfront high-dose therapy with autologous stem cell transplant (HDT/ASCT) on outcome in adult ALCL and PTCL-NOS patients according to their ALK, DUSP22 and TP63 status. The survival results from the two published series were pooled with those of a Nordic Lymphoma Group trial, the NLG-T-01 (d'Amore et al, JCO 2012), where patients were treated with 1st line CHOEP/CHOP followed, in chemosensitive cases, by upfront HDT/ASCT. Methods: Fluorescence in situ hybridization was performed on sections of previously constructed tissue microarrays using break-apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion [inv(3)(q26q28)]. Evaluation of DUSP22 and TP63 rearrangements was performed in a blinded fashion without knowledge of PTCL subtype, clinical course, or outcome. Three independent patient cohorts were included: (i) one from Mayo Clinic consisting of 31 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 25; TP63r+: 6); (ii) one from Denmark consisting of 93 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 90; TP63r+: 3); and one from the NLG-T-01 trial consisting of 46 ALK-ALCL and PTCL-NOS (triple negative: 37; TP63r+: 1; DUSP22r+: 8), leading to a total study population of 170 patients. ALK+ ALCL was not included in the analysis, since no patients with this histology entered the NLG-T-01 trial. Association of genetic subtype with OS was assessed using Kaplan-Meier curves and Cox proportional models for hazard rate ratios (HR). Significant differences were defined as P <0.05. Results: The eight DUSP22r+ patients (7 ALK-ALCL and 1 PTCL-NOS) from NLG-T-01 had a 5-yr OS of 83%, (95%CI 27-97), similar to that reported for DUSP22r+ in the Mayo and Danish cohorts (90% and 80%, respectively). No lymphoma-related events were observed in this subset. The only event was a septic death due to HDT-induced cytopenias in a patient who was in complete remission (CR). Among the 162 patients with DUSP22r-, ALK-ALCL and PTCL-NOS, those consolidated with HDT/ASCT (n=47) had a significantly better outcome (5-yr OS: 45%) than those treated with induction chemotherapy alone (5-yr OS: 30%) (n=115) (P=0.01). The patients in the HDT/ASCT group were younger (P<0.001) and had more advanced stage disease (P=0.002). The improvement in OS persisted when the analysis was limited to transplant eligible patients and adjusted for age and stage (HR 0.52 95%CI 29-91, P=0.023) or International Prognostic Index (IPI) groups (HR 0.49, 95%CI 20-82, P=0.006). Of the 10 TP63r+ patients found within the pooled cohort, 6 were transplant eligible. Of these, 5 were not transplanted (intention-to-treat) while one was (Nordic trial). The latter patient achieved a still ongoing long-term CR, while all others died of lymphoma progression. Conclusion: In ALK-ALCL and PTCL-NOS patients from the NLG-T-01 trial, DUSP22r+ was associated with a very good outcome, similar to that seen in DUSP22r+ patients who had not undergone upfront autologous transplant. This observation supports the impression that upfront HDT/ASCT may not be of benefit in these patients. TP63r+ predicted poor outcome in non-transplanted patients. The impact of HDT/ASCT in the TP63r+ setting could not be adequately evaluated, since only one patient from the NLG-T-01 trial cohort was found to be TP63r+. Notably, this patient was the only survivor of the TP63r+ subset. For DUSP22r-, ALK-ALCL and PTCL-NOS patients taken as one group, those who received upfront HDT/ASCT had a superior survival compared to their age- and IPI-matched non-transplanted counterparts. Disclosures Ellin: ROCHE: Consultancy, Research Funding; CTI: Consultancy. Mannisto: Roche: Honoraria, Other: Travel expence; Takeda: Honoraria, Other: Travel expence; Amgen: Other: Travel expence; Novartis: Other: Travel expence; Celgene: Other: Travel expence; Gilead: Other: Travel expence; Pfizer: Honoraria; SOBI: Honoraria. Cerhan: Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering . Toldbod: Takeda Pharma: Honoraria.
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Hirose, Jun, Hironari Masuda, Naoto Tokuyama, Yasunori Omata, Takumi Matsumoto, Tetsuro Yasui, Yuho Kadono, Lothar Hennighausen i Sakae Tanaka. "Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast". Journal of Experimental Medicine 211, nr 1 (23.12.2013): 153–63. http://dx.doi.org/10.1084/jem.20130538.
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Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal–related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.
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Liu, Xuejiao, Xuenan Liu, Yangge Du, Menglong Hu, Yueming Tian, Zheng Li, Longwei Lv i in. "DUSP5 Promotes Osteogenic Differentiation Through SCP1/2-Dependent Phosphorylation of SMAD1". Stem Cells 39, nr 10 (10.07.2021): 1395–409. http://dx.doi.org/10.1002/stem.3428.
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Abstract Dual-specificity phosphatases (DUSPs) are defined by their capability to dephosphorylate both phosphoserine/phosphothreonine (pSer/pThr) and phosphotyrosine (pTyr). DUSP5, a member of DUSPs superfamily, is located in the nucleus and plays crucially regulatory roles in the signaling pathway transduction. In our present study, we discover that DUSP5 significantly promotes osteogenic differentiation of mesenchymal stromal cells (MSCs) by activating SMAD1 signaling pathway. Mechanistically, DUSP5 physically interacts with the phosphatase domain of small C-terminal phosphatase 1/2 (SCP1/2, SMAD1 phosphatases) by the linker region. In addition, we further confirm that DUSP5 activates SMAD1 signaling through a SCP1/2-dependent manner. Specifically, DUSP5 attenuates the SCP1/2-SMAD1 interaction by competitively binding to SCP1/2, which is responsible for the SMAD1 dephosphorylation, and thus results in the activation of SMAD1 signaling. Importantly, DUSP5 expression in mouse bone marrow MSCs is significantly reduced in ovariectomized (OVX) mice in which osteogenesis is highly passive, and overexpression of Dusp5 via tail vein injection reverses the bone loss of OVX mice efficiently. Collectively, this work demonstrates that the linker region of DUSP5 maybe a novel chemically modifiable target for controlling MSCs fate choices and for osteoporosis treatment.
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Gém, Janka Borbála, Kinga Bernadett Kovács, Laura Szalai, Gyöngyi Szakadáti, Edit Porkoláb, Bence Szalai, Gábor Turu i in. "Characterization of Type 1 Angiotensin II Receptor Activation Induced Dual-Specificity MAPK Phosphatase Gene Expression Changes in Rat Vascular Smooth Muscle Cells". Cells 10, nr 12 (15.12.2021): 3538. http://dx.doi.org/10.3390/cells10123538.
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Activation of the type I angiotensin receptor (AT1-R) in vascular smooth muscle cells (VSMCs) plays a crucial role in the regulation of blood pressure; however, it is also responsible for the development of pathological conditions such as vascular remodeling, hypertension and atherosclerosis. Stimulation of the VSMC by angiotensin II (AngII) promotes a broad variety of biological effects, including gene expression changes. In this paper, we have taken an integrated approach in which an analysis of AngII-induced gene expression changes has been combined with the use of small-molecule inhibitors and lentiviral-based gene silencing, to characterize the mechanism of signal transduction in response to AngII stimulation in primary rat VSMCs. We carried out Affymetrix GeneChip experiments to analyze the effects of AngII stimulation on gene expression; several genes, including DUSP5, DUSP6, and DUSP10, were identified as upregulated genes in response to stimulation. Since various dual-specificity MAPK phosphatase (DUSP) enzymes are important in the regulation of mitogen-activated protein kinase (MAPK) signaling pathways, these genes have been selected for further analysis. We investigated the kinetics of gene-expression changes and the possible signal transduction processes that lead to altered expression changes after AngII stimulation. Our data shows that the upregulated genes can be stimulated through multiple and synergistic signal transduction pathways. We have also found in our gene-silencing experiments that epidermal growth factor receptor (EGFR) transactivation is not critical in the AngII-induced expression changes of the investigated genes. Our data can help us understand the details of AngII-induced long-term effects and the pathophysiology of AT1-R. Moreover, it can help to develop potential interventions for those symptoms that are induced by the over-functioning of this receptor, such as vascular remodeling, cardiac hypertrophy or atherosclerosis.
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Ham, Ji-Eun, Eun-Kyung Oh, Dong-Hoon Kim i Sang-Hyun Choi. "Differential expression profiles and roles of inducible DUSPs and ERK1/2-specific constitutive DUSP6 and DUSP7 in microglia". Biochemical and Biophysical Research Communications 467, nr 2 (listopad 2015): 254–60. http://dx.doi.org/10.1016/j.bbrc.2015.09.180.
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Hiratsuka, Toru, Ignacio Bordeu, Gunnar Pruessner i Fiona M. Watt. "Regulation of ERK basal and pulsatile activity control proliferation and exit from the stem cell compartment in mammalian epidermis". Proceedings of the National Academy of Sciences 117, nr 30 (10.07.2020): 17796–807. http://dx.doi.org/10.1073/pnas.2006965117.
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Fluctuation in signal transduction pathways is frequently observed during mammalian development. However, its role in regulating stem cells has not been explored. Here we tracked spatiotemporal ERK MAPK dynamics in human epidermal stem cells. While stem cells and differentiated cells were distinguished by high and low stable basal ERK activity, respectively, we also found cells with pulsatile ERK activity. Transitions from Basalhi-Pulselo(stem) to Basalhi-Pulsehi, Basalmid-Pulsehi, and Basallo-Pulselo(differentiated) cells occurred in expanding keratinocyte colonies and in response to differentiation stimuli. Pharmacological inhibition of ERK induced differentiation only when cells were in the Basalmid-Pulsehistate. Basal ERK activity and pulses were differentially regulated by DUSP10 and DUSP6, leading us to speculate that DUSP6-mediated ERK pulse down-regulation promotes initiation of differentiation, whereas DUSP10-mediated down-regulation of mean ERK activity promotes and stabilizes postcommitment differentiation. Levels of MAPK1/MAPK3 transcripts correlated with DUSP6 and DUSP10 transcripts in individual cells, suggesting that ERK activity is negatively regulated by transcriptional and posttranslational mechanisms. When cells were cultured on a topography that mimics the epidermal−dermal interface, spatial segregation of mean ERK activity and pulses was observed. In vivo imaging of mouse epidermis revealed a patterned distribution of basal cells with pulsatile ERK activity, and down-regulation was linked to the onset of differentiation. Our findings demonstrate that ERK MAPK signal fluctuations link kinase activity to stem cell dynamics.
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Nallaparaju, Kalyan, Yongliang Zhang, Xikui Liu, Joseph Reynolds, Roza Nurieva i Chen Dong. "DUSP11 is required for innate immunity (167.4)". Journal of Immunology 188, nr 1_Supplement (1.05.2012): 167.4. http://dx.doi.org/10.4049/jimmunol.188.supp.167.4.
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Abstract Dual specificity phosphatases (DUSPs) have been shown to play a critical role in regulation of various cellular processes. DUSP11 was previously demonstrated to bind to RNA-RNP complexes and RNA splicing factors and is a p53 target gene. Our in vitro studies showed that DUSP11 expression is induced in dendritic cells (DCs) upon stimulation by TLR ligands and in T cells upon CD3/CD28 activation suggesting the prominence of DUSP11 in immune responses. To examine the function of DUSP11 in regulating immune responses, we generated and analyzed DUSP11 deficient mice. We found that DUSP11 deficient antigen presenting cells produce decreased levels of proinflammatory cytokines during innate immune responses and CD4 T cells showed increased proliferation after activation but no apparent defect in in vitro T cell differentiation. However, our in vivo experiments demonstrated that DUSP11 deficient mice are defective in antigen-specific T cell responses and that they are more susceptible to Listeria monocytogenes infection. Using DC and T cell co-culture experiments we established that the DUSP11 signalling in DCs eventually regulates CD4 T cell activation. Together, these results demonstrate the critical role of DUSP11 in innate immunity.
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Ashraf, Sadia, Yassmin K. Hegazy i Romain Harmancey. "Nuclear receptor subfamily 4 group A member 2 inhibits activation of ERK signaling and cell growth in response to β-adrenergic stimulation in adult rat cardiomyocytes". American Journal of Physiology-Cell Physiology 317, nr 3 (1.09.2019): C513—C524. http://dx.doi.org/10.1152/ajpcell.00526.2018.
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Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and left ventricular contractile dysfunction in chronic heart failure. The orphan nuclear receptor NR4A2 is an immediate early-response gene activated in the heart under β-adrenergic stimulation. The goal of this study was to identify the transcriptional remodeling events induced by increased NR4A2 expression in cardiomyocytes and their impact on the physiological response of those cells to sustained β-adrenergic stimulation. Treatment of adult rat ventricular myocytes with isoproterenol induced a rapid (<4 h) increase in NR4A2 levels that was accompanied by a transient (<24 h) increase in nuclear localization of the transcription factor. Adenovirus-mediated overexpression of NR4A2 to similar levels modulated the expression of genes linked to adrenoceptor signaling, calcium signaling, cell growth and proliferation and counteracted the increase in protein synthesis rate and cell surface area mediated by chronic isoproterenol stimulation. Consistent with those findings, NR4A2 overexpression also blocked the phosphorylative activation of growth-related kinases ERK1/2, Akt, and p70 S6 kinase. Prominent among the transcriptional changes induced by NR4A2 was the upregulation of the dual-specificity phosphatases DUSP2 and DUSP14, two known inhibitors of ERK1/2. Pretreatment of NR4A2-overexpressing cardiomyocytes with the DUSP inhibitor BCI [( E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1 H-inden-1-one] prevented the inhibition of ERK1/2 following isoproterenol stimulation. In conclusion, our results suggest that NR4A2 acts as a novel negative feedback regulator of the β-adrenergic receptor-mediated growth response in cardiomyocytes and this at least partly through DUSP-mediated inhibition of ERK1/2 signaling.
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Broderick, S. R., D. Chitale, N. Motoi, Y. Gong, W. Pao, E. Venkatraman, V. Rusch, C. Brennan, W. Gerald i M. Ladanyi. "Integrated genomic analysis of lung adenocarcinomas identifies loss of the MAPK phosphatase gene DUSP4 in most EGFR mutant tumors". Journal of Clinical Oncology 25, nr 18_suppl (20.06.2007): 7686. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7686.
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7686 Background: Genomic analyses of lung adenocarcinoma have yielded striking advances that are already impacting on clinical management. Further advances in understanding the biological heterogeneity of this disease will require integration of multiple types of genomic data. To this end, we have assembled a large integrated genomics dataset of lung adenocarcinomas. Here, we highlight one of the novel findings emerging from its initial analysis. Methods: 173 primary lung adenocarcinomas were included in this analysis. Profiling of genomic gains and losses was done by array comparative genomic hybridization (aCGH) on Agilent 44K arrays. Expression profiling was based on Affymetrix U133A arrays. The dataset was annotated for EGFR mutations (exon 19 deletion and L858R) by sensitive PCR-based assays and for KRAS mutations by sequencing. Results: By unsupervised analysis of the aCGH data, the 173 tumors clustered robustly into two or three patterns of co-occurring gains and losses. One aCGH cluster was strongly associated with EGFR mutation (p<10−4) and was characterized by 7p gains (in the EGFR region) and 8p losses. Remarkably, by expression profiling the most consistently underexpressed gene (p<10−9) in EGFR mutant cases compared to EGFR wild type cases was a MAPK phosphatase gene at 8p12, DUSP4 (MKP-2). The DUSP4 region showed genomic loss in 27/35 EGFR mutant cases vs 47/138 non-mutated cases (p<10−4). A limited screen (n=11) has so far revealed no DUSP4 mutations. Western blotting shows low DUSP4 in most EGFR mutant lines, compared to KRAS mutant lines. Conclusions: EGFR mutations in lung adenocarcinomas are strongly associated with genomic loss and low expression of DUSP4. DUSPs are known to be transcriptionally upregulated by MAPK signaling as a negative feedback mechanism and DUSP family members are emerging as putative tumor suppressors in other cancers. We hypothesize that DUSP4 loss cooperates with EGFR mutation to allow full oncogenic activation of the MAPK pathway. Functional studies of DUSP4 in lung adenocarcinoma cell lines are in progress. Our data highlight the value of large, integrated, highly annotated genomic datasets in generating novel insights and hypotheses. No significant financial relationships to disclose.
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Ferguson, Bradley S., Sara A. Wennersten, Kimberly M. Demos-Davies, Marcello Rubino, Emma L. Robinson, Maria A. Cavasin, Matthew S. Stratton i in. "DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy". American Journal of Physiology-Heart and Circulatory Physiology 321, nr 2 (1.08.2021): H382—H389. http://dx.doi.org/10.1152/ajpheart.00115.2021.
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Dual-specificity phosphatases (DUSPs) serve critical roles in the regulation of mitogen-activated protein kinases, but their functions in the cardiovascular system remain poorly defined. Here, we provide evidence that DUSP5, which resides in the nucleus and specifically dephosphorylates extracellular signal-regulated kinase (ERK1/2), blocks pulmonary vascular smooth muscle cell proliferation. In response to angiotensin II infusion, mice lacking DUSP5 develop pulmonary hypertension and right ventricular cardiac hypertrophy. These findings illustrate DUSP5-mediated suppression of ERK signaling in the lungs as a protective mechanism.
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Bulle, Ashenafi Shiferaw, Kuljeet Seehar, Sapana Bansod, Yali Chen, Chen Hung-Po, Paarth B. Dodhiawala, Lin Li i in. "Abstract 5333: Pancreatic cancer enhances HER2 signaling through DUSP6 to circumvent therapeutic MAPK inhibition". Cancer Research 82, nr 12_Supplement (15.06.2022): 5333. http://dx.doi.org/10.1158/1538-7445.am2022-5333.
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Abstract Background: Oncogenic KRAS is present in almost all cases of pancreatic ductal adenocarcinoma (PDAC). However, targeting KRAS or its canonical signaling cascades, especially the mitogen-activated protein kinase (MAPK) pathway, remains clinically unsuccessful. Targeting ERK kinases has recently emerged as a promising therapeutic strategy and combinatorial strategies should be developed. Aim: Identify adaptive mechanisms to ERK inhibition that can be co-targeted to achieve effective tumor inhibition in multiple patient-derived xenograft (PDX) models. Methods: Reverse-phase protein array (RPPA) was used in early-passage patient-derived cell lines (PDCLs) to identify potential resistance mechanisms. These were confirmed using RNA interference and overexpression in PDAC cell lines and PDCLs. The promising combinations were tested in 30 early-passaged PDAC PDXs. Results: RPPA showed dramatic downregulation of DUSP4 and DUSP6 phosphatases following MEK and ERK inhibition, which coincided with upregulation of phospho-HER2 and -HER3. Knockdown of DUSP6, but not DUSP4, was sufficient in phosphorylation of HER2. Conversely, overexpression of DUSP6 curbed HER2 and ERK activation. Downregulation of DUSP4 and DUSP6 induced by ulixertinib, an ERK inhibitor now in clinical development, was reversed by bortezomib, suggesting DUSP4 and DUSP6 are proteosomally degraded. Combined ulixertinib plus PI3K inhibitor copanlisib, or pan-HER inhibitor afatinib slowed but did not arrest PDX tumor growth in vivo, and addition of gemcitabine was required to achieve tumor regression or durable growth arrest. Alternatively, ulixertinib or MEK inhibitor (trametinib) in combination with trastuzumab deruxtecan (DS-8201a), an anti-HER2 conjugated topoisomerase I inhibitor, were extremely effective, leading to complete and durable tumor regression for all tested PDX models. We showed that upregulation of HER2 expression following MEK or ERK inhibitor treatment provides a conduit for enhanced internalization of DS-8201a. Conclusions: Our study provided novel mechanistic insight on how PDAC cells evade MAPK inhibition via enhancing HER2 signaling. We demonstrated that the combination of MEK or ERK inhibitor plus DS-8201a is extremely effective, leading to complete tumor regression in multiple PDAC PDX models. This combination should be advanced as a clinical trial for PDAC patients. Keys: DS-8201a, DUSP6, HER2, KRAS, ulixertinib, pancreatic ductal adenocarcinoma Citation Format: Ashenafi Shiferaw Bulle, Kuljeet Seehar, Sapana Bansod, Yali Chen, Chen Hung-Po, Paarth B. Dodhiawala, Lin Li, Vikas Somani, Jacqueline Mudd, Ryan C. Fields, Deborah Knoerzer, Andrea Wang-Gillam, Lim Kian-Huat. Pancreatic cancer enhances HER2 signaling through DUSP6 to circumvent therapeutic MAPK inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5333.
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Wang, Mike, Nour Kibbi, Nan Ring, Alexa Siddon, Francine Foss i Mariam Totonchy. "DUSP22-IRF4 rearrangement in AIDS-associated ALK-negative anaplastic large cell lymphoma". BMJ Case Reports 12, nr 9 (wrzesień 2019): e230641. http://dx.doi.org/10.1136/bcr-2019-230641.
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Patients with AIDS have increased risk of developing lymphomas, such as anaplastic large cell lymphoma (ALCL), which generally carry a poor prognosis. The DUSP-IRF4 genetic rearrangement in ALCL confers a favourable prognosis in HIV-negative patients; it is unknown how this interacts clinically with HIV/AIDS. A man aged 53 years presented with subcutaneous nodules on the scalp and axillae, and diffuse lymphadenopathy. Biopsy of subcutaneous nodule and lymph node showed large atypical anaplastic lymphocytes which were CD30+ and anaplastic lymphoma kinase-negative, consistent with primary systemic ALCL. In addition, he was found to be HIV-positive and diagnosed with AIDS. Genetic testing of the tissue revealed a DUSP22-IRF4 rearrangement. Complete remission was achieved with HyperCVAD and subsequent brentuximab vedotin monotherapy. We report a case of AIDS-associated primary systemic ALCL with a DUSP22-IRF4 rearrangement. AIDS-associated ALCL is an aggressive lymphoma, with a poor prognosis. However, the presence of the genetic rearrangement, previously unseen in this disease, drastically altered the disease course. This case highlights the value of genetic testing and identifies DUSP22-IRF4-associated ALCL in the setting of HIV-associated lymphoproliferative disorders.
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He, Jiayang, Yijie Cai, Wei Huang, Yunxiang Lin, Yurong Lei, Cuifen Huang, Zongbin Cui, Qiwei Qin i Hongyan Sun. "The Role of Epinephelus coioides DUSP5 in Regulating Singapore Grouper Iridovirus Infection". Viruses 15, nr 9 (25.08.2023): 1807. http://dx.doi.org/10.3390/v15091807.
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The dual-specificity phosphatase (DUSP) family plays an important role in response to adverse external factors. In this study, the DUSP5 from Epinephelus coioides, an important marine fish in Southeast Asia and China, was isolated and characterized. As expected, E. coioides DUSP5 contained four conserved domains: a rhodanese homology domain (RHOD); a dual-specificity phosphatase catalytic domain (DSPc); and two regions of low compositional complexity, indicating that E. coioides DUSP5 belongs to the DUSP family. E. coioides DUSP5 mRNA could be detected in all of the examined tissues, and was mainly distributed in the nucleus. Infection with Singapore grouper iridovirus (SGIV), one of the most important pathogens of marine fish, could inhibit the expression of E. coioides DUSP5. The overexpression of DUSP5 could significantly downregulate the expression of the key SGIV genes (MCP, ICP18, VP19, and LITAF), viral titers, the activity of NF-κB and AP-I, and the expression of pro-inflammatory factors (IL-6, IL-8, and TNF-α) of E. coioides, but could upregulate the expressions of caspase3 and p53, as well as SGIV-induced apoptosis. The results demonstrate that E. coioides DUSP5 could inhibit SGIV infection by regulating E. coioides immune-related factors, indicating that DUSP5 might be involved in viral infection.
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Kujur, Weshely, Oscar Murillo, SitaRamaRaju Adduri i Sachin Mulik. "Heterogeneity in NK memory stem cells after Zika virus infection using single cell approaches". Journal of Immunology 208, nr 1_Supplement (1.05.2022): 126.03. http://dx.doi.org/10.4049/jimmunol.208.supp.126.03.
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Abstract Zika virus infection during pregnancy causes congenital defects such as microcephaly and ocular pathologies. Our lab previously reported that Zika virus infection in mice induces memory like NK cells that express CD27, had higher TCF-1 levels and possessed superior antiviral ability than naïve CD27+ NK cells. Moreover, these cells revealed stem like properties. We termed those NK cells with memory and stem cell like features as “NK memory stem cells (NKSCM). We hypothesized that NKSCM may contain subpopulations that differ in stemness program and antiviral capacity. To determine this, we performed single cell RNA-seq on NKSCM cells. Our analysis revealed 8 distinct clusters in NKSCM. Of these, Cluster 0 showed upregulation of Dusp1, Dusp2, Junb, Fosb while cluster 4 showed downregulation of Dusp1, Dusp2, Junb, Fosb genes. Cluster 5 had upregulation of proliferation associated genes (Mki67, Cdk1 and Pcna). Cluster 3 revealed downregulation of cytotoxic genes (Prf1, Gzma, Gzmb) while gene upregulation of Id3, Myb, Sell, Cd226 and Cxcr3 was evident in this subset. Similarly, other clusters showed differential gene expression profiles. Currently, our analysis is ongoing for single cell ATAC-seq datasets to determine epigenome at single cell level in these NKSCM clusters. Finally, the experiments are underway to functionally characterize these NKSCM subpopulations and to evaluate their role in Zika viral defense. This work was supported by Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, TX, USA and American Association of Immunology Careers in Immunology Fellowship
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Pérez-Sen, Queipo, Gil-Redondo, Ortega, Gómez-Villafuertes, Miras-Portugal i Delicado. "Dual-Specificity Phosphatase Regulation in Neurons and Glial Cells". International Journal of Molecular Sciences 20, nr 8 (23.04.2019): 1999. http://dx.doi.org/10.3390/ijms20081999.
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Dual-specificity protein phosphatases comprise a protein phosphatase subfamily with selectivity towards mitogen-activated protein (MAP) kinases, also named MKPs, or mitogen-activated protein kinase (MAPK) phosphatases. As powerful regulators of the intensity and duration of MAPK signaling, a relevant role is envisioned for dual-specificity protein phosphatases (DUSPs) in the regulation of biological processes in the nervous system, such as differentiation, synaptic plasticity, and survival. Important neural mediators include nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) that contribute to DUSP transcriptional induction and post-translational mechanisms of DUSP protein stabilization to maintain neuronal survival and differentiation. Potent DUSP gene inducers also include cannabinoids, which preserve DUSP activity in inflammatory conditions. Additionally, nucleotides activating P2X7 and P2Y13 nucleotide receptors behave as novel players in the regulation of DUSP function. They increase cell survival in stressful conditions, regulating DUSP protein turnover and inducing DUSP gene expression. In general terms, in the context of neural cells exposed to damaging conditions, the recovery of DUSP activity is neuroprotective and counteracts pro-apoptotic over-activation of p38 and JNK. In addition, remarkable changes in DUSP function take place during the onset of neuropathologies. The restoration of proper DUSP levels and recovery of MAPK homeostasis underlie the therapeutic effect, indicating that DUSPs can be relevant targets for brain diseases.
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Ju, Gaoda, Tianhao Zhou, Rui Zhang, Xiaozao Pan, Bing Xue i Sen Miao. "DUSP12 regulates the tumorigenesis and prognosis of hepatocellular carcinoma". PeerJ 9 (3.08.2021): e11929. http://dx.doi.org/10.7717/peerj.11929.
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Background Dual specificity protein phosphatase (DUSP)12 is an atypical member of the protein tyrosine phosphatase family, which are overexpressed in multiple types of malignant tumors. This protein family protect cells from apoptosis and promotes the proliferation and motility of cells. However, the pathological role of DUSP12 in hepatocellular carcinoma (HCC) is incompletely understood. Methods We analyzed mRNA expression of DUSP12 between HCC and normal liver tissues using multiple online databases, and explored the status of DUSP12 mutants using the cBioPortal database. The correlation between DUSP12 expression and tumor-infiltrating immune cells was demonstrated using the Tumor Immune Estimation Resource database and the Tumor and Immune System Interaction Database. Loss of function assay was utilized to evaluate the role of DUSP12 in HCC progression. Results DUSP12 had higher expression along with mRNA amplification in HCC tissues compared with those in normal liver tissues, which suggested that higher DUSP12 expression predicted shorter overall survival. Analyses of functional enrichment of differentially expressed genes suggested that DUSP12 regulated HCC tumorigenesis, and that knockdown of DUSP12 expression by short hairpin (sh)RNA decreased the proliferation and migration of HCC cells. Besides, DUSP12 expression was positively associated with the infiltration of cluster of differentiation (CD)4+ T cells (especially CD4+ regulatory T cells), macrophages, neutrophils and dendritic cells. DUSP12 expression was positively associated with immune-checkpoint moieties, and was downregulated in a C3 immune-subgroup of HCC (which had the longest survival). Conclusion These data suggest that DUSP12 may have a critical role in the tumorigenesis, infiltration of immune cells, and prognosis of HCC.
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Ejima, Aki, Shinya Abe, Akihiro Shimba, Susumu Sato, Takuya Uehata, Shizue Tani-ichi, Satoru Munakata i in. "Androgens Alleviate Allergic Airway Inflammation by Suppressing Cytokine Production in Th2 Cells". Journal of Immunology 209, nr 6 (15.09.2022): 1083–94. http://dx.doi.org/10.4049/jimmunol.2200294.
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Abstract Asthma is more common in females than males after adolescence. However, the mechanism of the sex bias in the prevalence of asthma remains unknown. To test whether sex steroid hormones have some roles in T cells during development of asthma, we analyzed airway inflammation in T cell–specific androgen receptor (AR)– and estrogen receptor (ER)–deficient mice. T cell–specific AR-deficient male mice developed severer house dust mite–induced allergic airway inflammation than did control male mice, whereas T cell–specific ERα- and ERβ-deficient female mice exhibited a similar degree of inflammation as for control female mice. Furthermore, administration of dihydrotestosterone reduced cytokine production of Th2 cells from control, but not AR-deficient, naive T cells. Transfer of OT-II transgenic AR-deficient Th2 cells into wild-type mice induced severer allergic airway inflammation by OVA than transfer of control Th2 cells. Gene expression profiling suggested that the expression of genes related with cell cycle and Th2 differentiation was elevated in AR-deficient Th2 cells, whereas expression of dual specificity phosphatase (DUSP)-2, a negative regulator of p38, was downregulated. In addition, a chromatin immunoprecipitation assay suggested that AR bound to an AR motif in the 5′ untranslated region of the Dusp2 gene in Th2 cells. Furthermore, the Dusp2 promoter with a wild-type AR motif, but not a mutated motif, was transactivated by dihydrotestosterone in a reporter assay. Finally, forced expression of DUSP-2 by retrovirus vector reduced IL-4 expression in Th2 cells. Thus, these results suggest that androgen signaling suppresses cytokine production of Th2 cells by inducing DUSP-2, explaining, in part, the sex bias of asthma after adolescence.
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Sladeček, Stanislava, Katarzyna Anna Radaszkiewicz, Martina Bőhmová, Tomáš Gybeľ, Tomasz Witold Radaszkiewicz i Jiří Pacherník. "Dual specificity phosphatase 7 drives the formation of cardiac mesoderm in mouse embryonic stem cells". PLOS ONE 17, nr 10 (13.10.2022): e0275860. http://dx.doi.org/10.1371/journal.pone.0275860.
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Dual specificity phosphatase 7 (DUSP7) is a protein belonging to a broad group of phosphatases that can dephosphorylate phosphoserine/phosphothreonine as well as phosphotyrosine residues within the same substrate. DUSP7 has been linked to the negative regulation of mitogen activated protein kinases (MAPK), and in particular to the regulation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). MAPKs play an important role in embryonic development, where their duration, magnitude, and spatiotemporal activity must be strictly controlled by other proteins, among others by DUSPs. In this study, we focused on the effect of DUSP7 depletion on the in vitro differentiation of mouse embryonic stem (ES) cells. We showed that even though DUSP7 knock-out ES cells do retain some of their basic characteristics, when it comes to differentiation, they preferentially differentiate towards neural cells, while the formation of early cardiac mesoderm is repressed. Therefore, our data indicate that DUSP7 is necessary for the correct formation of neuroectoderm and cardiac mesoderm during the in vitro differentiation of ES cells.
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Kidger, Andrew M., Linda K. Rushworth, Julia Stellzig, Jane Davidson, Christopher J. Bryant, Cassidy Bayley, Edward Caddye, Tim Rogers, Stephen M. Keyse i Christopher J. Caunt. "Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling". Proceedings of the National Academy of Sciences 114, nr 3 (4.01.2017): E317—E326. http://dx.doi.org/10.1073/pnas.1614684114.
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Deregulated extracellular signal-regulated kinase (ERK) signaling drives cancer growth. Normally, ERK activity is self-limiting by the rapid inactivation of upstream kinases and delayed induction of dual-specificity MAP kinase phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that, although the MKP DUSP5 both inactivates and anchors ERK in the nucleus, it paradoxically increases and prolongs cytoplasmic ERK activity. The latter effect is caused, at least in part, by the relief of ERK-mediated RAF inhibition. The importance of this spatiotemporal interaction between these distinct feedback mechanisms is illustrated by the fact that expression of oncogenic BRAFV600E, a feedback-insensitive mutant RAF kinase, reprograms DUSP5 into a cell-wide ERK inhibitor that facilitates cell proliferation and transformation. In contrast, DUSP5 deletion causes BRAFV600E-induced ERK hyperactivation and cellular senescence. Thus, feedback interactions within the ERK pathway can regulate cell proliferation and transformation, and suggest oncogene-specific roles for DUSP5 in controlling ERK signaling and cell fate.
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Hua, Chunting, Qiaoli Zheng, Jiang Zhu, Siji Chen, Yinjing Song, Stijn van der Veen i Hao Cheng. "Human Papillomavirus Type 16 Early Protein E7 Activates Autophagy through Inhibition of Dual-Specificity Phosphatase 5". Oxidative Medicine and Cellular Longevity 2022 (10.03.2022): 1–19. http://dx.doi.org/10.1155/2022/1863098.
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Consistent high-risk human papillomavirus (HPV) infection leads to various malignant cancers. Autophagy can promote cancer progression by helping cancer cells survive under stress or induce oncogenic effects when mutations or abnormalities occur. Mitogen activated protein kinases (MAPKs) can transduce various external or intrinsic stimuli into cellular responses, including autophagy, and dual-specificity phosphates (DUSPs) contribute to the direct regulation of MAPK activities. Previously, we showed that expression of DUSP5 was repressed in HPV16 E7-expressing normal human epidermal keratinocytes (NHEKs). Here we show that clinical HPV16 E7-positive precancerous and cancerous tissues also demonstrate low DUSP5 levels compared with control tissues, indicating that the inverse correlation between HPV16 E7 and DUSP5 is clinically relevant. We furthermore investigated the autophagy response in both DUSP5-deficient and HPV16 E7-expressing NHEKs. Confocal microscopy and Western analysis showed induction of LC3-II levels, autophagosome formation and autophagy fluxes in DUSP5-deficient NHEKs. Furthermore, Western analysis demonstrated specific induction of phosphorylated ERK in DUSP5-deficient and HPV16 E7-expressing NHEKs, indicating that HPV16 E7-mediated repression of DUSP5 results in induced MAPK/ERK signaling. Finally, phosphorylated mTOR and ULK (S757) were reduced in DUSP5-deficient NHEKs, while phosphorylated ULK (S555) and AMPK were increased, thereby inducing canonical autophagy through the mTOR and AMPK pathways. In conclusion, our results demonstrate that HPV16 E7 expression reduces DUSP5 levels, which in turn results in active MAPK/ERK signaling and induction of canonical autophagy through mTOR and MAPK regulation. Given its demonstrated inverse correlation with clinical cancerous tissues, DUSP5 may serve as a potential therapeutic target for cervical cancer.
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Jeong, Dae Gwin, Chun Hua Wei, Bonsu Ku, Tae Jin Jeon, Pham Ngoc Chien, Jae Kwan Kim, So Ya Park i in. "The family-wide structure and function of human dual-specificity protein phosphatases". Acta Crystallographica Section D Biological Crystallography 70, nr 2 (29.01.2014): 421–35. http://dx.doi.org/10.1107/s1399004713029866.
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Dual-specificity protein phosphatases (DUSPs), which dephosphorylate both phosphoserine/threonine and phosphotyrosine, play vital roles in immune activation, brain function and cell-growth signalling. A family-wide structural library of human DUSPs was constructed based on experimental structure determination supplemented with homology modelling. The catalytic domain of each individual DUSP has characteristic features in the active site and in surface-charge distribution, indicating substrate-interaction specificity. The active-site loop-to-strand switch occurs in a subtype-specific manner, indicating that the switch process is necessary for characteristic substrate interactions in the corresponding DUSPs. A comprehensive analysis of the activity–inhibition profile and active-site geometry of DUSPs revealed a novel role of the active-pocket structure in the substrate specificity of DUSPs. A structure-based analysis of redox responses indicated that the additional cysteine residues are important for the protection of enzyme activity. The family-wide structures of DUSPs form a basis for the understanding of phosphorylation-mediated signal transduction and the development of therapeutics.
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Román-García, Pablo, Natalia Carrillo-López, Manuel Naves-Díaz, Isabel Rodríguez, Alberto Ortiz i Jorge B. Cannata-Andía. "Dual-Specificity Phosphatases Are Implicated in Severe Hyperplasia and Lack of Response to FGF23 of Uremic Parathyroid Glands from Rats". Endocrinology 153, nr 4 (14.02.2012): 1627–37. http://dx.doi.org/10.1210/en.2011-1770.
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Phosphate load accelerates the progression of secondary hyperparathyroidism (sHPT). In advanced stages of sHPT, there is a marked hyperplasia and resistance to classical regulatory endocrine factors such as calcium, calcitriol, or fibroblast growth factor 23 (FGF23), which suppresses PTH secretion by an ERK-dependent mechanism. Nephrectomized rats were fed with a high- or normal-phosphorus diet for different periods of time to induce sHPT. Biochemical parameters, parathyroid gland microarrays, quantitative real-time PCR, and immunohistochemistry (ERK/phospho-ERK) were performed. To test the role of dual-specificity phosphatases (Dusp) on parathyroid gland regulation, normal parathyroid glands were cultured with FGF23 and Dusp. Uremic rats fed with a high-phosphorus diet showed more severe sHPT, higher serum FGF23 levels and mortality, and decreased parathyroid Klotho gene expression. In all stages of sHPT, parathyroid microarrays displayed a widespread gene expression down-regulation; only a few genes were overexpressed, among them, Dusp5 and -6. In very severe sHPT, a significant reduction in phospho-ERK (the target of Dusp) and a significant increase of Dusp5 and -6 gene expression were observed. In ex vivo experiments with parathyroid glands, Dusp partially blocked the effect of FGF23 on PTH secretion, suggesting that Dusp might play a role in parathyroid regulation. The overexpression of Dusp and the inactivation of ERK found in the in vivo studies together with the ex vivo results might be indicative of the defense mechanism triggered to counteract hyperplasia, a mechanism that can also contribute to the resistance to the effect of FGF23 on parathyroid gland observed in advanced forms of chronic kidney disease.
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Wilczek, Michael P., Francesca J. Armstrong, Remi P. Geohegan, Colleen L. Mayberry, Jeanne K. DuShane, Benjamin L. King i Melissa S. Maginnis. "The MAPK/ERK Pathway and the Role of DUSP1 in JCPyV Infection of Primary Astrocytes". Viruses 13, nr 9 (14.09.2021): 1834. http://dx.doi.org/10.3390/v13091834.
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JC polyomavirus (JCPyV) is a neuroinvasive pathogen causing a fatal, demyelinating disease of the central nervous system (CNS) known as progressive multifocal leukoencephalopathy (PML). Within the CNS, JCPyV predominately targets two cell types: oligodendrocytes and astrocytes. The underlying mechanisms of astrocytic infection are poorly understood, yet recent findings suggest critical differences in JCPyV infection of primary astrocytes compared to a widely studied immortalized cell model. RNA sequencing was performed in primary normal human astrocytes (NHAs) to analyze the transcriptomic profile that emerges during JCPyV infection. Through a comparative analysis, it was validated that JCPyV requires the mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK/ERK) pathway, and additionally requires the expression of dual-specificity phosphatases (DUSPs). Specifically, the expression of DUSP1 is needed to establish a successful infection in NHAs, yet this was not observed in an immortalized cell model of JCPyV infection. Additional analyses demonstrated immune activation uniquely observed in NHAs. These results support the hypothesis that DUSPs within the MAPK/ERK pathway impact viral infection and influence potential downstream targets and cellular pathways. Collectively, this research implicates DUSP1 in JCPyV infection of primary human astrocytes, and most importantly, further resolves the signaling events that lead to successful JCPyV infection in the CNS.
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Tsai, Hao-Yu, Henkie Isahwan Ahmad Mulyadi Lai, Zhang-Yuan Chen, Tai-Chi Lin, Winnie Khor, Wen-Chuan Kuo, Jia-Pu Syu i in. "Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro". Biomedicines 10, nr 1 (12.01.2022): 159. http://dx.doi.org/10.3390/biomedicines10010159.
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Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase (ERK) pathway. However, the complex interplay between DUSP6 and autophagy induced by ROS in RPE is yet to be investigated. To investigate the relationship between DUSP6 and autophagy, we exposed the ARPE-19 cell line and C57BL/6N mice to sodium iodate (NaIO3) as an oxidative stress inducer. Our data showed that the inhibition of DUSP6 activity promotes autophagy flux through the ERK pathway via the upregulation of immunoblotting expression in ARPE-19 cells. Live imaging showed a significant increase in autophagic flux activities, which suggested the restoration autophagy after treatment with the DUSP6 inhibitor. Furthermore, the mouse RPE layer exhibited an irregular structure and abnormal deposits following NaIO3 injection. The retina layer was recovered after being treated with DUSP6 inhibitor; this suggests that DUSP6 inhibitor can rescue retinal damage by restoring the mouse retina’s autophagy flux. This study suggests that the upregulation of DUSP6 can cause autophagy flux malfunctions in the RPE. The DUSP6 inhibitor can restore autophagy induction, which may serve as a potential therapeutic approach for retinal degeneration disease.
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Chuang, Huai-Chia, i Tse-Hua Tan. "DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated immune responses by inactivating a transcriptional repressor". Journal of Immunology 210, nr 1_Supplement (1.05.2023): 243.04. http://dx.doi.org/10.4049/jimmunol.210.supp.243.04.
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Abstract Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivorole of DUSP8 in T cells remains unclear. Using T-cell-specific DUSP8 conditional knockout (T-DUSP8 cKO, DUSP8 f/f;CD4-Cre) mice, mass spectrometry, and chromatin-immunoprecipitation sequencing, we found that DUSP8 stimulated interleukin-9 (IL-9) gene expression and Th9 differentiation. TGF-β stimulated DUSP8 phosphatase activity in T cells. Mechanistically, DUSP8 dephosphorylated a transcriptional repressor upon TGF-β signaling, leading to the nuclear export of this transcriptional repressor and subsequent IL-9 transcriptional activation. Reduction of IL-9 mRNA levels in T cells of T-DUSP8 cKO mice was reversed by knocking out the transcriptional repressor in double knockout mice. Furthermore, IL-9 mRNA levels were induced in T cells lacking the transcriptional repressor. In addition, T-DUSP8 cKO mice displayed a reduction of IL-9 and Th9-mediated immune responses of allergy, autoimmune responses, and anti-tumor immunity in animal models. In contrast, the reduced allergy phenotype in T-DUSP8 cKO mice was reversed by knocking out the transcriptional repressor in double knockout mice. Collectively, DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated immune responses by promoting the nuclear export of a transcriptional repressor.
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Leyva-Illades, Dinorah, Rama P. Cherla, Cristi L. Galindo, Ashok K. Chopra i Vernon L. Tesh. "Global Transcriptional Response of Macrophage-Like THP-1 Cells to Shiga Toxin Type 1". Infection and Immunity 78, nr 6 (29.03.2010): 2454–65. http://dx.doi.org/10.1128/iai.01341-09.
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ABSTRACT Shiga toxins (Stxs) are bacterial cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli that cause bacillary dysentery and hemorrhagic colitis, respectively. To date, approaches to studying the capacity of Stxs to alter gene expression in intoxicated cells have been limited to individual genes. However, it is known that many of the signaling pathways activated by Stxs regulate the expression of multiple genes in mammalian cells. To expand the scope of analysis of gene expression and to better understand the underlying mechanisms for the various effects of Stxs on host cell functions, we carried out comparative microarray analyses to characterize the global transcriptional response of human macrophage-like THP-1 cells to Shiga toxin type 1 (Stx1) and lipopolysaccharides. The data were analyzed by using a rigorous combinatorial approach with three separate statistical algorithms. A total of 36 genes met the criteria of upregulated expression in response to Stx1 treatment, with 14 genes uniquely upregulated by Stx1. Microarray data were validated by real-time reverse transcriptase PCR for genes encoding early growth response 1 (Egr-1) (transcriptional regulator), cyclooxygenase 2 (COX-2; inflammation), and dual specificity phosphatase 1 (DUSP1), DUSP5, and DUSP10 (regulation of mitogen-activated protein kinase signaling). Stx1-mediated signaling through extracellular signal-regulated kinase 1/2 and Egr-1 appears to be involved in the increased expression and production of the proinflammatory mediator tumor necrosis factor alpha. Activation of COX-2 is associated with the increased production of proinflammatory and vasoactive eicosanoids. However, the capacity of Stx1 to increase the expression of genes encoding phosphatases suggests that mechanisms to dampen the macrophage proinflammatory response may be built into host response to the toxins.