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https://www.readbyqxmd.com/read/28053233/dual-specificity-phosphatase-5-controls-the-localized-inhibition-propagation-and-transforming-potential-of-erk-signaling
#1
Andrew M Kidger, Linda K Rushworth, Julia Stellzig, Jane Davidson, Christopher J Bryant, Cassidy Bayley, Edward Caddye, Tim Rogers, Stephen M Keyse, Christopher J Caunt
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...
January 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27997807/roflumilast-n-oxide-in-combination-with-formoterol-enhances-the-anti-inflammatory-effect-of-dexamethasone-in-asm-cells
#2
Brijeshkumar S Patel, Md Mostafizur Rahman, Gina Baehring, Dikaia Xenaki, Francesca Su-May Tang, Brian G Oliver, Alaina J Ammit
Roflumilast is an orally active phosphodiesterase 4 (PDE4) inhibitor approved for use in chronic obstructive pulmonary disease. Roflumilast N-oxide (RNO) is the active metabolite of roflumilast and has demonstrated anti-inflammatory impact in vivo and in vitro. To date, the effect of RNO on the synthetic function of airway smooth muscle (ASM) cells is unknown. We address this herein and investigate the effect of RNO on β2-adrenoceptor-mediated, cAMP-dependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation...
December 20, 2016: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27958388/map-kinase-phosphatase-2-deficient-mice-develop-attenuated-experimental-autoimmune-encephalomyelitis-through-regulating-dendritic-cells-and-t-cells
#3
Mark Barbour, Robin Plevin, Hui-Rong Jiang
Mitogen-activated protein kinase phosphatases (MKPs) play key roles in inflammation and immune mediated diseases. Here we investigated the mechanisms by which MKP-2 modulates central nervous system (CNS) inflammation in experimental autoimmune encephalomyelitis (EAE). Our results show that MKP-2 mRNA levels in the spinal cord and lymphoid organs of EAE mice were increased compared with naive controls, indicating an important role for MKP-2 in EAE development. Indeed, MKP-2(-/-) mice developed reduced EAE severity, associated with diminished CNS immune cell infiltration, decreased proinflammatory cytokine production and reduced frequency of CD4(+) and CD8(+) T cells in spleens and lymph nodes...
December 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27913746/anti-trachea-inflammatory-effects-of-diosgenin-from-dioscorea-nipponica-through-interactions-with-glucocorticoid-receptor-%C3%AE
#4
Yang Junchao, Wang Zhen, Wang Yuan, Xu Liying, Jiang Libin, Zhu Yuanhong, Zhao Wei, Chen Ruilin, Zhai Lu
Asthma is a heterogeneous disease characterized by symptoms of chronic inflammation and airway structural and functional changes. It affects about 300 million people worldwide and causes 250 000 deaths annually, but its symptoms can be greatly relieved by regular use of inhaled glucocorticoids (GCs). GCs exert their function through interacting with glucocorticoid receptors (GRs). Diosgenin is a naturally occurring steroidal saponin abundantly present in many medicinal plants, including Dioscorea nipponica, which shares a similar steroidal structure with GC...
December 2, 2016: Journal of International Medical Research
https://www.readbyqxmd.com/read/27852250/impaired-anti-inflammatory-action-of-glucocorticoid-in-neutrophil-from-patients-with-steroid-resistant-asthma
#5
Meijia Wang, Pengfei Gao, Xiaojie Wu, Yuetao Chen, Yikuan Feng, Qun Yang, Yongjian Xu, Jianping Zhao, Jungang Xie
BACKGROUND: Steroid resistant (SR) asthma is characterized by persistent airway inflammation that fails to resolve despite treatment with high doses of corticosteroids. Furthermore, SR patient airways show increased numbers neutrophils, which are less responsive to glucocorticoid. The present study seeks to determine whether dexamethasone (DEX) has different effect on neutrophils from steroid sensitive (SS) asthmatics compared to SR asthmatics. METHODS: Adults with asthma (n = 38) were classified as SR or SS based on changes in lung FEV1% following a one-month inhaled corticosteroid (ICS) treatment...
November 16, 2016: Respiratory Research
https://www.readbyqxmd.com/read/27783995/mkp-1-attenuates-lps-induced-blood-testis-barrier-dysfunction-and-inflammatory-response-through-p38-and-i%C3%AE%C2%BAb%C3%AE-pathways
#6
Yiqing Pan, Yue Liu, Li Wang, Feng Xue, Yanqin Hu, Ran Hu, Chen Xu
Sertoli cells create a local tolerogenic microenvironment to maintain testicular immune privilege especially through the formation of a blood-testis barrier (BTB). However, the molecular mechanisms underlying the immune modulation function and BTB dynamics of Sertoli cells remained elusive. MAP phosphatase (MKP)-1 acts as a crucial negative regulator of the inflammatory response. Nevertheless, the role of MKP-1 in regulating Sertoli cells has not been elucidated. In this study, we have for the first time uncovered distinct cellular localization of MKP-1 in the cells at different stages of mouse testis, and the level of MKP-1 expression was significantly up-regulated by LPS-induced acute testis inflammation...
October 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27771897/profiling-of-signaling-proteins-in-penumbra-after-focal-photothrombotic-infarct-in-the-rat-brain-cortex
#7
Svetlana Demyanenko, Anatoly Uzdensky
In ischemic stroke, cell damage propagates from infarct core to surrounding tissue. To reveal proteins involved in neurodegeneration and neuroprotection, we explored the protein profile in penumbra surrounding the photothrombotic infarct core induced in rat cerebral cortex by local laser irradiation after Bengal Rose administration. Using antibody microarrays, we studied changes in expression of 224 signaling proteins 1, 4, or 24 h after photothrombotic infarct compared with untreated contralateral cortex...
October 22, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27771463/upregulation-of-mkp-7-in-response-to-rosiglitazone-treatment-ameliorates-lipopolysaccharide-induced-destabilization-of-sirt1-by-inactivating-jnk
#8
Jung Seok Hwang, Sun Ah Ham, Taesik Yoo, Won Jin Lee, Kyung Shin Paek, Jae-Hwan Kim, Chi-Ho Lee, Han Geuk Seo
Silent mating type information regulation 2 homolog 1 (SIRT1), a NAD-dependent deacetylase, mediates cellular processes involved in gene silencing and aging. The regulation of lifespan by SIRT1 has been extensively investigated, but less is known about the mechanisms associated with its cellular turnover during inflammatory responses. In this study, we found that peroxisome proliferator-activated receptor (PPAR) γ is associated with SIRT1 stability in murine macrophage RAW 264.7 cells exposed to lipopolysaccharide (LPS)...
December 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27677845/resveratrol-suppresses-nthi-induced-inflammation-via-up-regulation-of-the-negative-regulator-myd88-short
#9
Carla S Andrews, Shingo Matsuyama, Byung-Cheol Lee, Jian-Dong Li
Upper respiratory tract inflammatory diseases such as asthma and chronic obstructive pulmonary diseases (COPD) affect more than one-half billion people globally and are characterized by chronic inflammation that is often exacerbated by respiratory pathogens such as nontypeable Haemophilus influenzae (NTHi). The increasing numbers of antibiotic-resistant bacterial strains and the limited success of currently available pharmaceuticals used to manage the symptoms of these diseases present an urgent need for the development of novel anti-inflammatory therapeutic agents...
September 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27670844/monocytic-mkp-1-is-a-sensor-of-the-metabolic-environment-and-regulates-function-and-phenotypic-fate-of-monocyte-derived-macrophages-in-atherosclerosis
#10
Hong Seok Kim, Sina Tavakoli, Leigh Ann Piefer, Huynh Nga Nguyen, Reto Asmis
Diabetes promotes the S-glutathionylation, inactivation and subsequent degradation of mitogen-activated protein kinase phosphatase 1 (MKP-1) in blood monocytes, and hematopoietic MKP-1-deficiency in atherosclerosis-prone mice accelerates atherosclerotic lesion formation, but the underlying mechanisms were not known. Our aim was to determine the mechanisms through which MKP-1 deficiency in monocytes and macrophages promotes atherogenesis. Transplantation of MKP-1-deficient bone marrow into LDL-R(-/-) (MKP-1LeuKO) mice accelerated high-fat diet (HFD)-induced atherosclerotic lesion formation...
September 27, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27620528/4-hydroxy-2-nonenal-induces-apoptosis-by-activating-erk1-2-signaling-and-depleting-intracellular-glutathione-in-intestinal-epithelial-cells
#11
Yun Ji, Zhaolai Dai, Guoyao Wu, Zhenlong Wu
Excessive reactive oxygen species (ROS) induces oxidative damage to cellular constituents, ultimately leading to induction of apoptotic cell death and the pathogenesis of various diseases. The molecular mechanisms for the action of ROS in intestinal diseases remain poorly defined. Here, we reported that 4-hydroxy-2-nonenal (4-HNE) treatment led to capses-3-dependent apoptosis accompanied by increased intracellular ROS level and reduced glutathione concentration in intestinal epithelial cells. These effects of 4-HNE were markedly abolished by the antioxidant L-cysteine derivative N-acetylcysteine (NAC)...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27599524/c-jun-n-terminal-kinase-inactivation-by-mitogen-activated-protein-kinase-phosphatase-1-determines-resistance-to-taxanes-and-anthracyclines-in-breast-cancer
#12
Raul Rincon, Sandra Zazo, Cristina Chamizo, Rebeca Manso, Paula González-Alonso, Ester Martin-Aparicio, Ion Cristobal, Carmen Cañadas, Rosario Perona, Ana Lluch, Pilar Eroles, Jesus Garcia-Foncillas, Joan Albanell, Ana Rovira, Juan Madoz-Gurpide, Federico Rojo
Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is overexpressed during malignant transformation of the breast in many patients, and it is usually associated with chemoresistance through interference with JNK-driven apoptotic pathways. Although the molecular settings of the mechanism have been documented, details about the contribution of MKP-1 to the failure of chemotherapeutic interventions are unclear. Transient overexpression of MKP-1 and treatment with JNK-modulating agents in breast carcinoma cells confirmed the mediation of MKP-1 in the resistance to taxanes and anthracyclines in breast cancer, through the inactivation of JNK½...
September 6, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27548147/growth-hormone-releasing-peptide-2-attenuation-of-protein-kinase-c-induced-inflammation-in-human-ovarian-granulosa-cells
#13
Yi-Ning Chao, David Sun, Yen-Chun Peng, Yuh-Lin Wu
Cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) are two important inflammatory mediators in ovulation. Ghrelin may modulate inflammatory signaling via growth hormone secretagogue receptors. We investigated the role of ghrelin in KGN human ovarian granulosa cells using protein kinase C (PKC) activator phorbol 12, 13-didecanoate (PDD) and synthetic ghrelin analog growth hormone releasing peptide-2 (GHRP-2). GHRP-2 attenuated PDD-induced expression of protein and mRNA, the promoter activity of COX-2 and IL-8 genes, and the secretion of prostaglandin E2 (PGE₂) and IL-8...
August 19, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27538525/curcumin-suppresses-nthi-induced-cxcl5-expression-via-inhibition-of-positive-ikk%C3%AE-pathway-and-up-regulation-of-negative-mkp-1-pathway
#14
Anuhya S Konduru, Byung-Cheol Lee, Jian-Dong Li
Otitis media (OM) is the most common childhood bacterial infection, and leading cause of conductive hearing loss. Nontypeable Haemophilus influenzae (NTHi) is a major bacterial pathogen for OM. OM characterized by the presence of overactive inflammatory responses is due to the aberrant production of inflammatory mediators including C-X-C motif chemokine ligand 5 (CXCL5). The molecular mechanism underlying induction of CXCL5 by NTHi is unknown. Here we show that NTHi up-regulates CXCL5 expression by activating IKKβ-IκBα and p38 MAPK pathways via NF-κB nuclear translocation-dependent and -independent mechanism in middle ear epithelial cells...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27514808/visualizing-and-quantitating-the-spatiotemporal-regulation-of-ras-erk-signaling-by-dual-specificity-mitogen-activated-protein-phosphatases-mkps
#15
Christopher J Caunt, Andrew M Kidger, Stephen M Keyse
The spatiotemporal regulation of the Ras/ERK pathway is critical in determining the physiological and pathophysiological outcome of signaling. Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (DUSPs or MKPs) are key regulators of pathway activity and may also localize ERK to distinct subcellular locations. Here we present methods largely based on the use of high content microscopy to both visualize and quantitate the subcellular distribution of activated (p-ERK) and total ERK in populations of mouse embryonic fibroblasts derived from mice lacking DUSP5, a nuclear ERK-specific MKP...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27477309/tlr2-ligation-induces-corticosteroid-insensitivity-in-a549-lung-epithelial-cells-anti-inflammatory-impact-of-pp2a-activators
#16
Md Mostafizur Rahman, Pavan Prabhala, Nowshin N Rumzhum, Brijeshkumar S Patel, Thomas Wickop, Philip M Hansbro, Nicole M Verrills, Alaina J Ammit
Corticosteroids are effective anti-inflammatory therapies widely utilized in chronic respiratory diseases. But these medicines can lose their efficacy during respiratory infection resulting in disease exacerbation. Further in vitro research is required to understand how infection worsens lung function control in order to advance therapeutic options to treat infectious exacerbation in the future. In this study, we utilize a cellular model of bacterial exacerbation where we pretreat A549 lung epithelial cells with the synthetic bacterial lipoprotein Pam3CSK4 (a TLR2 ligand) to mimic bacterial infection and tumor necrosis factor α (TNFα) to simulate inflammation...
September 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27459239/role-for-dusp1-dual-specificity-protein-phosphatase-1-in-the-regulation-of-autophagy
#17
Juan Wang, Jun-Ying Zhou, Dhonghyo Kho, John J Reiners, Gen Sheng Wu
Accumulating evidence suggests that mitogen-activated protein kinases (MAPKs) regulate macroautophagy/autophagy. However, the involvement of dual-specificity protein phosphatases (DUSPs), endogenous inhibitors for MAPKs, in autophagy remains to be determined. Here we report that DUSP1/MKP-1, the founding member of the DUSP family, plays a critical role in regulating autophagy. Specifically, we demonstrate that DUSP1 knockdown by shRNA in human ovarian cancer CAOV3 cells and knockout in murine embryonic fibroblasts, increases both basal and rapamycin-increased autophagic flux...
October 2, 2016: Autophagy
https://www.readbyqxmd.com/read/27454161/bmi1-inhibits-senescence-and-enhances-the-immunomodulatory-properties-of-human-mesenchymal-stem-cells-via-the-direct-suppression-of-mkp-1-dusp1
#18
Jin Young Lee, Kyung-Rok Yu, Hyung-Sik Kim, Insung Kang, Jae-Jun Kim, Byung-Chul Lee, Soon Won Choi, Ji-Hee Shin, Yoojin Seo, Kyung-Sun Kang
For the application of mesenchymal stem cells (MSCs) as clinical therapeutics, the regulation of cellular aging is important to protect hMSCs from an age-associated decline in their function. In this study, we evaluated the effects of hypoxia on cellular senescence and the immunomodulatory abilities of hUCB-MSCs. Hypoxic-cultured hUCB-MSCs showed enhanced proliferation and had increased immunosuppressive effects on mitogen-induced mononuclear cell proliferation. We found that BMI1, a member of the polycomb repressive complex protein group, showed increased expression in hypoxic-cultured hUCB-MSCs, and the further knock-down of BMI1 in hypoxic cells induced decreased proliferative and immunomodulatory abilities in hUCB-MSCs, along with COX-2/PGE2 down-regulation...
August 2016: Aging
https://www.readbyqxmd.com/read/27446931/mitogen-activated-protein-kinases-and-mitogen-kinase-phosphatase-1-a-critical-interplay-in-macrophage-biology
#19
REVIEW
Jorge Lloberas, Lorena Valverde-Estrella, Juan Tur, Tania Vico, Antonio Celada
Macrophages are necessary in multiple processes during the immune response or inflammation. This review emphasizes the critical role of the mitogen-activated protein kinases (MAPKs) and mitogen kinase phosphatase-1 (MKP-1) in the functional activities of macrophages. While the phosphorylation of MAPKs is required for macrophage activation or proliferation, MKP-1 dephosphorylates these kinases, thus playing a balancing role in the control of macrophage behavior. MKP-1 is a nuclear-localized dual-specificity phosphatase whose expression is regulated at multiple levels, including at the transcriptional and post-transcriptional level...
2016: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/27375556/role-of-protein-phosphorylation-and-tyrosine-phosphatases-in-the-adrenal-regulation-of-steroid-synthesis-and-mitochondrial-function
#20
REVIEW
Cristina Paz, Fabiana Cornejo Maciel, Alejandra Gorostizaga, Ana F Castillo, M Mercedes Mori Sequeiros García, Paula M Maloberti, Ulises D Orlando, Pablo G Mele, Cecilia Poderoso, Ernesto J Podesta
In adrenocortical cells, adrenocorticotropin (ACTH) promotes the activation of several protein kinases. The action of these kinases is linked to steroid production, mainly through steroidogenic acute regulatory protein (StAR), whose expression and activity are dependent on protein phosphorylation events at genomic and non-genomic levels. Hormone-dependent mitochondrial dynamics and cell proliferation are functions also associated with protein kinases. On the other hand, protein tyrosine dephosphorylation is an additional component of the ACTH signaling pathway, which involves the "classical" protein tyrosine phosphatases (PTPs), such as Src homology domain (SH) 2-containing PTP (SHP2c), and members of the MAP kinase phosphatase (MKP) family, such as MKP-1...
2016: Frontiers in Endocrinology
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