Dual-Specificity Phosphatases as Molecular Targets for Inhibition in Human Disease

Ríos, Pablo; Nunes‐Xavier, Caroline E.; Tabernero, Lydia; Köhn, Maja; Pulido, Rafael

doi:10.1089/ars.2013.5709

Cited by 75 publications

(67 citation statements)

References 205 publications

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“…6, B-D), we questioned how hypoxiainduced ROS enhanced JNK activity. Because the catalytic cysteine in DUSPs have an unusually low pK a , they are highly sensitive to oxidation and inactivation (37). Therefore, many stimuli that trigger ROS production in cells can transiently induce the oxidation and inactivation of DUSPs, leading to enhanced MAPK signaling.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to potential oxidation of the catalytic cysteine, various DUSPs use a non-catalytic regulatory cysteine to bind the catalytic cysteine, thereby reversibly inactivating the enzyme and protecting it from irreversible oxidation (37). Amino acid alignment of DUSP16 shows that it contains a putative redox-regulatory cysteine in proximity to the catalytic cysteine (37), suggesting that hypoxia may modulate DUSP16 activity through either direct oxidation of the catalytic cysteine or through a non-catalytic redox-regulatory mechanism. Although ROS-induced oxidation of DUSP1 has been reported in endothelial cells (36), our data showed a 13.3-fold induction of DUSP1 compared with only a 1.8-fold induction of DUSP16 following hypoxic palmitate treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The catalytic cysteine is highly sensitive to oxidation and inactivation under conditions of elevated ROS production, such as hypoxia (36,37). Therefore, we questioned whether enhanced palmitate-induced JNK activity and cytokine production under hypoxia were mediated through reduced JNK-specific MAPK phosphatase activity.…”

Section: Dual-specificity Phosphatase 16 (Dusp16) Negatively Regulatementioning

confidence: 99%

“…Therefore, we questioned whether enhanced palmitate-induced JNK activity and cytokine production under hypoxia were mediated through reduced JNK-specific MAPK phosphatase activity. For this reason, we focused on DUSP16, because of its reported specificity for JNK in macrophages (37,38), and on DUSP1, a well characterized component of inflammatory signaling in immune cells (39,40). To examine their roles, we transfected macrophages with DUSP16-or DUSP1-specific siRNA.…”

Section: Dual-specificity Phosphatase 16 (Dusp16) Negatively Regulatementioning

confidence: 99%

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Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

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Pro-inflammatory cytokines secreted by adipose tissue macrophages (ATMs) contribute to chronic low-grade inflammation and obesity-induced insulin resistance. Recent studies have shown that adipose tissue hypoxia promotes an inflammatory phenotype in ATMs. However, our understanding of how hypoxia modulates the response of ATMs to free fatty acids within obese adipose tissue is limited. We examined the effects of hypoxia (1% O 2 ) on the pro-inflammatory responses of human monocyte-derived macrophages to the saturated fatty acid palmitate. Compared with normoxia, hypoxia significantly increased palmitate-induced mRNA expression and protein secretion of IL-6 and IL-1␤. Although palmitate-induced endoplasmic reticulum stress and nuclear factor B pathway activation were not enhanced by hypoxia, hypoxia increased the activation of JNK and p38 mitogen-activated protein kinase signaling in palmitate-treated cells. Inhibition of JNK blocked the hypoxic induction of pro-inflammatory cytokine expression, whereas knockdown of hypoxia-induced transcription factors HIF-1␣ and HIF-2␣ alone or in combination failed to reduce IL-6 and only modestly reduced IL-1␤ gene expression in palmitate-treated hypoxic macrophages. Enhanced pro-inflammatory cytokine production and JNK activity under hypoxia were prevented by inhibiting reactive oxygen species generation. In addition, silencing of dual-specificity phosphatase 16 increased normoxic levels of IL-6 and IL-1␤ and reduced the hypoxic potentiation in palmitate-treated macrophages. The secretome of hypoxic palmitate-treated macrophages promoted IL-6 and macrophage chemoattractant protein 1 expression in primary human adipocytes, which was sensitive to macrophage JNK inhibition. Our results reveal that the coexistence of hypoxia along with free fatty acids exacerbates macrophage-mediated inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Dual-specificity Phosphatase 16 (Dusp16) Negatively Regulatementioning

confidence: 99%

Section: Dual-specificity Phosphatase 16 (Dusp16) Negatively Regulatementioning

confidence: 99%

See 2 more Smart Citations

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

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“…DUSPs can be sub-divided into functional groups: typical and atypical DUSPs with or without an additional MAP kinase binding (MKB) domain [14]. Similar to this category, DUSPs also can be classified by their specific functions: oncogenic or anti-cancer effect in various cancer cells [15][16][17][18][19]. Our previous reports suggest that DUSP28 promotes malignancy of pancreatic cancer through various signaling pathways including intracellular signaling regulation and synchronized expression modification of other molecules [15,20].…”

Section: Introductionmentioning

confidence: 99%

Contribution of DUSP28 to Regulation of Mucins in Human Pancreatic Cancer Cells

Lee¹,

Kim²

2017

Adv Tech Biol Med

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Pancreatic cancer remains one of the most deadly cancers, and once diagnosed, the prognosis for patient survival is poor. Patient outcomes have not been improved despite considerable and continuous efforts. We have suggested that dual-specificity phosphatase 28 (DUSP28) is a potential anti-cancer target to inhibit malignant pancreatic cancers. In this context, atypical DUSP28 can affect the regulation of mucins such as mucin5B (MUC5B) and mucin16 (MUC16). To investigate this correlation, we analysed mRNA levels of DUSP28 and mucins using the Gene Expression Omnibus public microarray database in pancreatic cancer, which indicated higher DUSP28, MUC1, MUC4, MUC5B, MUC16 and MUC20 mRNA levels in pancreatic cancers compared with normal pancreas tissue. In addition, DUSP28 expression in human pancreatic cancers correlated positively with those of MUC1, MUC4, MUC5B, MUC16 and MUC20. In contrast, there were no significant correlations between DUSP28 and mucins in normal pancreas tissues. Decreased DUSP28 expression resulted in down regulation of MUC5B and MUC16 at both the mRNA and protein levels. Furthermore, blockade of MUC5B or MUC16 expression inhibited migration and survival of cancer cells through the inhibition of phosphorylated FAK and ERK1/2. Collectively, we propose that DUSP28 uniquely links regulation of MUC5B and MUC16 to migration and survival of pancreatic cancer cells, which strongly support a rationale for targeting DUSP28 to inhibit development of malignant pancreatic cancer.

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Downregulation of JKAP is correlated with elevated disease risk, advanced disease severity, higher inflammation, and poor survival in sepsis

Zhao

Huang

2019

Clinical Laboratory Analysis

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ObjectiveThis study aimed to explore the association of JKAP with sepsis risk and investigate its correlation with disease severity, inflammatory cytokines, and survival in sepsis patients.MethodsA hundred and one sepsis patients along with 100 healthy controls were enrolled, and their blood serum samples were collected for JKAP and inflammatory cytokines measurement by enzyme‐linked immunoassay. The difference in serum JKAP between sepsis patients and healthy controls was determined. Among sepsis patients, the correlation of JKAP with disease severity, laboratory indexes, inflammatory cytokines, 28‐day mortality, and accumulating survival was analyzed.ResultsJNK pathway–associated phosphatase level was decreased in sepsis patients compared with healthy controls and presented with good value in predicting decreased sepsis risk (AUC = 0.896 [95% CI: 0.851‐0.941]). And its low expression was associated with advanced disease severity (APACHE II score and SOFA score) and systemic inflammation (CRP, PCT, TNF‐α, IL‐1β, IL‐6, and IL‐17) in sepsis patients. Additionally, JKAP level was decreased in deaths compared with survivors and had good value in distinguishing deaths from survivors (AUC = 0.742 [95% CI: 0.636‐0.849]). Further, Kaplan‐Meier curve analysis disclosed that JKAP high expression predicted more prolonged accumulating survival in sepsis patients.ConclusionJNK pathway–associated phosphatase is of good value in predicting lower sepsis risk, and its downregulation correlates with advanced disease severity, higher level of systemic inflammation, and poor survival in sepsis patients.

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Dual-Specificity Phosphatases as Molecular Targets for Inhibition in Human Disease

Abstract: Further work is required to understand the dual role of many DUSPs in human cancer, their function-structure properties, and to identify their physiologic substrates. This will help in the implementation of therapies based on DUSPs inhibition.

Cited by 75 publications

References 205 publications

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Contribution of DUSP28 to Regulation of Mucins in Human Pancreatic Cancer Cells

Downregulation of JKAP is correlated with elevated disease risk, advanced disease severity, higher inflammation, and poor survival in sepsis

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