ABSTRACT
BACKGROUND: Dual specificity phosphatase 22 (DUSP22), also named as Jun N-terminal kinase pathway associated phosphatase recently, is reported to be closely engaged in immune and inflammation regulation. This study aimed to investigate the interaction between synovium DUSP22 and serum DUSP22 levels and to explore their correlation with rheumatoid arthritis (RA) risk, inflammation, and disease activity. METHODS: Synovium and serum samples from 42 RA patients with knee involvement underwent arthroscopy, and 20 knee trauma patients were collected. Besides, serum samples from 40 healthy controls were also obtained. Synovium DUSP22 expression was detected by reverse transcription quantitative polymerase chain reaction, while serum DUSP22 level was detected by enzyme-linked immunosorbent assay. RESULTS: Synovium DUSP22 level was greatly decreased in RA patients compared to trauma controls (p < 0.001), and it was negatively correlated with tender joint count (TJC) (r = -0.318, p = 0.040), C-reactive protein (CRP) (r = -0.330, p = 0.033), and Lysholm score (r = -0.423, p = 0.005) in RA patients. Serum DUSP22 level was lowest in RA patients, followed by trauma controls, then highest in healthy controls (p < 0.001). Serum DUSP22 level was negatively associated with TJC (r = -0.438, p = 0.004), swollen joint count (SJC) (r = -0.372, p = 0.015), CRP (r = -0.391, p = 0.011), and disease activity score in 28 joints (DAS28ESR ) score (r = -0.406, p = 0.008), and it increased after treatment (p = 0.001) in RA patients. In addition, serum DUSP22 level positively related to synovium DUSP22 level in RA patients (r = 0.394, p = 0.010). CONCLUSION: Synovium and serum DUSP22 are intercorrelated and insufficiently expressed in RA patients; meanwhile, their deficiency correlates with increased systemic inflammation, disease activity, and joint dysfunction.
Subject(s)
Arthritis, Rheumatoid , Dual-Specificity Phosphatases/analysis , Mitogen-Activated Protein Kinase Phosphatases/analysis , Synovial Membrane/chemistry , Aged , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/metabolism , Biomarkers/analysis , Biomarkers/blood , Dual-Specificity Phosphatases/blood , Dual-Specificity Phosphatases/metabolism , Female , Humans , Male , Middle Aged , Mitogen-Activated Protein Kinase Phosphatases/blood , Mitogen-Activated Protein Kinase Phosphatases/metabolismABSTRACT
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.
Subject(s)
Dual-Specificity Phosphatases/metabolism , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Animals , Dual-Specificity Phosphatases/analysis , Dual-Specificity Phosphatases/genetics , Humans , Mitogen-Activated Protein Kinase Phosphatases/analysis , Mitogen-Activated Protein Kinase Phosphatases/genetics , Models, Molecular , Neoplasms/genetics , Neoplasms/metabolism , Protein Conformation , Protein Interaction Maps , Substrate Specificity , Transcriptional ActivationABSTRACT
Background and objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disease that results in severe dementia. Having ischemic strokes (IS) is one of the risk factors of the AD, but the molecular mechanisms that underlie IS and AD are not well understood. We thus aimed to identify common molecular biomarkers and pathways in IS and AD that can help predict the progression of these diseases and provide clues to important pathological mechanisms. Materials and Methods: We have analyzed the microarray gene expression datasets of IS and AD. To obtain robust results, combinatorial statistical methods were used to analyze the datasets and 26 transcripts (22 unique genes) were identified that were abnormally expressed in both IS and AD. Results: Gene Ontology (GO) and KEGG pathway analyses indicated that these 26 common dysregulated genes identified several altered molecular pathways: Alcoholism, MAPK signaling, glycine metabolism, serine metabolism, and threonine metabolism. Further protein-protein interactions (PPI) analysis revealed pathway hub proteins PDE9A, GNAO1, DUSP16, NTRK2, PGAM2, MAG, and TXLNA. Transcriptional and post-transcriptional components were then identified, and significant transcription factors (SPIB, SMAD3, and SOX2) found. Conclusions: Protein-drug interaction analysis revealed PDE9A has interaction with drugs caffeine, γ-glutamyl glycine, and 3-isobutyl-1-methyl-7H-xanthine. Thus, we identified novel putative links between pathological processes in IS and AD at transcripts levels, and identified possible mechanistic and gene expression links between IS and AD.
Subject(s)
Alzheimer Disease/blood , Biomarkers/blood , Brain Ischemia/blood , 3',5'-Cyclic-AMP Phosphodiesterases/analysis , 3',5'-Cyclic-AMP Phosphodiesterases/blood , Alzheimer Disease/complications , Biomarkers/analysis , Brain Ischemia/complications , Dual-Specificity Phosphatases/analysis , Dual-Specificity Phosphatases/blood , GTP-Binding Protein alpha Subunits, Gi-Go/analysis , GTP-Binding Protein alpha Subunits, Gi-Go/blood , Humans , Membrane Glycoproteins/analysis , Membrane Glycoproteins/blood , Mitogen-Activated Protein Kinase Phosphatases/analysis , Mitogen-Activated Protein Kinase Phosphatases/blood , Myelin-Associated Glycoprotein/analysis , Myelin-Associated Glycoprotein/blood , Receptor, trkB/analysis , Receptor, trkB/blood , Signal Transduction/physiology , Stroke/blood , Stroke/complications , Vesicular Transport Proteins/analysis , Vesicular Transport Proteins/bloodABSTRACT
Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. Dual specificity phosphatase 4 (DUSP4) has recently been suggested as a potential marker of chemotherapy resistance for TNBC. DUSP4 gene expression levels were measured in breast cancer tissue from 469 TNBC patients aged 20-75 years who participated in the Shanghai Breast Cancer Survival Study, and their association with recurrence/breast cancer mortality and total mortality was evaluated. Information on breast cancer diagnosis, treatment, and disease progression was collected via medical chart review and multiple in-person follow-up surveys. A Cox regression model was applied in the data analyses. Over a median follow-up of 5.3 years (range: 0.7-8.9 years), 100 deaths and 92 recurrences/breast cancer deaths were documented. Expression levels of transcript variant 1 (NM_001394) and transcript variant 2 (NM_057158) of the DUSP4 gene were studied and were highly correlated (r = 0.76). Low DUSP4 expression levels, particularly of variant 1, were associated with both increased recurrence/breast cancer mortality and increased overall mortality. Hazard ratios with adjustment for age at diagnosis and TNM stage associated with below versus above the median expression level were 1.97 (95 % confidence interval (CI): 1.27-3.05) for recurrence/breast cancer mortality and 2.09 (95 % CI: 1.38-3.17) for overall mortality. Additional adjustment for expression levels of MKI67 and TP53, common treatment types, breast cancer subtype, and grade did not materially alter the observed associations. Low DUSP4 expression levels predict recurrence and mortality in TNBC patients independently from known clinical and molecular predictors.
Subject(s)
Biomarkers, Tumor/genetics , Dual-Specificity Phosphatases/biosynthesis , Mitogen-Activated Protein Kinase Phosphatases/biosynthesis , Neoplasm Recurrence, Local/genetics , Triple Negative Breast Neoplasms/genetics , Adult , Aged , Dual-Specificity Phosphatases/analysis , Dual-Specificity Phosphatases/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Mitogen-Activated Protein Kinase Phosphatases/analysis , Mitogen-Activated Protein Kinase Phosphatases/genetics , Neoplasm Recurrence, Local/pathology , Proportional Hazards Models , Transcriptome , Triple Negative Breast Neoplasms/pathology , Young AdultABSTRACT
Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.
Subject(s)
Biomarkers, Tumor/metabolism , Dual-Specificity Phosphatases/metabolism , Mitochondria/drug effects , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Cell Fractionation , Cell Line, Tumor , Chemotherapy, Adjuvant , Cisplatin/pharmacology , Cisplatin/therapeutic use , Disease-Free Survival , Drug Resistance, Neoplasm , Dual-Specificity Phosphatases/analysis , Female , Gene Knockdown Techniques , Gene Knockout Techniques , Humans , MAP Kinase Signaling System/drug effects , Male , Mice , Middle Aged , Mitochondria/metabolism , Mitogen-Activated Protein Kinase Phosphatases/analysis , Neoplasms/mortality , Neoplasms/pathology , Xenograft Model Antitumor Assays , bcl-2-Associated X Protein/metabolismABSTRACT
Dual-specificity phosphatases (DUSPs) are enzymes that participate in the regulation of biological processes such as cell growth, differentiation, transcription and metabolism. A number of DUSPs are able to dephosphorylate phosphorylated serine, threonine and tyrosine residues on mitogen-activated protein kinases (MAPKs) and thus are also classified as MAPK phosphatases (MKPs). As an increasing number of DUSPs are being identified and characterized, there is a growing need to understand their biological activities at the molecular level. There is also significant interest in identifying DUSPs that could be potential targets for drugs that modulate MAPK-dependent signaling and immune responses, which have been implicated in a variety of maladies including cancer, infectious diseases and inflammatory disorders. Here, the overproduction, purification and crystal structure at 1.88 A resolution of human dual-specificity phosphatase 14, DUSP14 (MKP6), are reported. This structural information should accelerate the study of DUSP14 at the molecular level and may also accelerate the discovery and development of novel therapeutic agents.
Subject(s)
Dual-Specificity Phosphatases/analysis , Mitogen-Activated Protein Kinase Phosphatases/analysis , Amino Acid Sequence , Catalytic Domain , Cloning, Molecular , Crystallography, X-Ray , Dual-Specificity Phosphatases/genetics , Dual-Specificity Phosphatases/isolation & purification , Humans , Mitogen-Activated Protein Kinase Phosphatases/genetics , Mitogen-Activated Protein Kinase Phosphatases/isolation & purification , Molecular Conformation , Molecular Sequence Data , Sequence AlignmentABSTRACT
Destruction of tumor cells is a key function of natural killer (NK) cells. Previous studies have shown that tributyltin (TBT) can significantly reduce the lytic function of the human NK cells with accompanying increases in the phosphorylation (activation) states of the mitogen activated protein kinases (MAPKs), p44/42. The current studies examine the role of p44/42 activation in the TBT-induced reduction of NK-lytic function, by using MAPK kinase (MEK) inhibitors, PD98059 and U0126. A 1 h treatment with PD98059 or U0126 or both decreased the ability of NK cells to lyse K562 tumor cells. PD98059, U0126 or a combination of both inhibitors were able to completely block TBT-induced activation of p44/42. However, when p44/42 activation was blocked by the presence of PD98059, U0126 or the combination, subsequent exposure to TBT was still able to decrease the lytic function of NK cells. These results indicate that TBT-induced activation of p44/42 occurs via the activation of its upstream activator, MEK, and not by a TBT-induced inhibition of p44/42 phosphatase activity. Additionally, as lytic function was never completely blocked by MEK inhibitors, the results indicate that activation of p44/42 pathway is not solely responsible for the activation of lytic function of freshly isolated human NK cells. Finally, the results showed that TBT-induced activation of p44/42 is not solely responsible for the loss of lytic function.