DOCSLIB.ORG

Role of Apical Caspases and Glucocorticoid-Regulated Genes in Glucocorticoid- Induced Apoptosis of Pre-B Leukemic Cells1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Role of Apical Caspases and Glucocorticoid-Regulated Genes in Glucocorticoid- Induced Apoptosis of Pre-B Leukemic Cells1 [CANCER RESEARCH 63, 172–178, January 1, 2003] Role of Apical Caspases and Glucocorticoid-regulated Genes in Glucocorticoid- induced Apoptosis of Pre-B Leukemic Cells1 Sonia L. Planey,2 Marc T. Abrams,2 Noreen M. Robertson, and Gerald Litwack3 Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 ABSTRACT two major pathways of caspase activation have been described: the receptor-mediated extrinsic pathway and the mitochondrial-mediated Glucocorticoid (GC) sensitivity in hematopoietic cells requires the ac- intrinsic pathway. Caspase-8 and caspase-10 are initiators of the tivation and nuclear translocation of the glucocorticoid receptor (GR) and extrinsic pathway where they are activated in response to death the subsequent activation of caspases. To gain insight into the caspase cascade responsible for the execution phase of GC-induced apoptosis, 697 receptor engagement by ligands belonging to the TNF superfamily pre-B leukemic cells were stably transfected with dominant negative (6). The intrinsic pathway involves mitochondrial disruption by pro- forms of caspase-8, caspase-9, or caspase-10 and the caspase-8 inhibitor apoptotic Bcl-2 family members and consequent release of factors CrmA. We observed that inhibition of caspase-9 or caspase-10 activity, such as cytochrome c that promote caspase-9 activation (7). Both but not caspase-8, caused partial resistance of 697 cells to GC-induced pathways culminate in the activation of downstream effector apoptosis. Inhibition of multiple caspases through the use of specific caspase-3, caspase-6, and caspase-7 and can cooperate to enhance peptide inhibitors had an additive effect and caused complete resistance. apoptosis through caspase-8-mediated cleavage of Bid (8). To identify GR-regulated genes upstream of caspase activation in 697 We and others have observed that GC-induced apoptosis is asso- cells, we performed DNA microarray analysis. 113 genes were identified, ciated with release of cytochrome c from the mitochondria5 (9) and which were induced or repressed at least 3-fold by GC. Surprisingly, that Bcl-2 overexpression can delay (10) or inhibit this process (11), mitogen-activated protein kinase phosphatase-1 (MKP-1), a GR-induced gene in other cell types, was repressed 3-fold and correlated with an confirming a primary role for the intrinsic pathway. To this end, induction of JNK activity. These results suggest the involvement of mito- experiments using thymocytes from knockout mice have shown an gen activated protein kinases and apical caspase-9 and caspase-10 in the absolute requirement for caspase-9 and Apaf-1 (12) in GC-induced GC-induced apoptosis of pre-B lymphocytes. apoptosis but not for caspase-3 (13), suggesting redundancy among the effector caspases. We examined the involvement of apical caspases and GR-regulated genes in the GC-induced cell death of INTRODUCTION human 697 pre-B acute lymphoblastic leukemia cells. Using a com- bination of specific caspase inhibitors and stably transfected DN GCs4 are steroid hormones that have diverse tissue-specific effects caspase genes, we demonstrate a requirement for caspase-9 and involved in homeostasis and response to stress. Almost all of the caspase-10, but not caspase-8, in GC-induced apoptosis. biological consequences of exposure to GCs are mediated through the GC-induced apoptosis can be modulated by the transfection of GR, a ligand-activated transcription factor and member of the nuclear genes that affect the activity of the GR and related cofactors (e.g., receptor superfamily (1). In its unactivated state, the GR is complexed RAP46/Bag-1; Ref. 14) as well as by genes that affect functions of the with heat shock proteins and immunophilins (2). Upon binding hor- universal apoptotic machinery (e.g., Bcl-2). However, it is still unclear mone, the GR becomes activated by the ATP-dependent release of which specific GR-regulated genes are involved in the decision stage these associated proteins, inducing a conformational change in the of GC-induced apoptosis, downstream of the GR but upstream of receptor and resulting in its translocation into the nucleus. There, it caspase activation. Using microarray technology, we have found that regulates target gene expression by (a) activating or repressing tran- MKP-1, a GR-induced gene in other tissues, was strongly repressed in scription by direct binding to GREs in the promoters of specific genes 697 cells and correlated with an increase in JNK/stress-activated or (b) repressing transcription by binding to and inhibiting the func- protein kinase activity. Thus, GC-mediated cell death in 697 cells may tion of other transcription factors such as AP-1 and nuclear factor ␬B involve GR-dependent repression of MKP-1 and subsequent activa- (reviewed in Ref. 3). tion of the proapoptotic JNK pathway (reviewed in Ref. 15). GCs induce apoptosis in numerous cell types, including immature lymphocytes and various malignancies of lymphoid origin and thus have become one of the most common therapies for corresponding MATERIALS AND METHODS leukemias and lymphomas (4). Universally, apoptosis is mediated through the activation of caspases. These aspartate-specific cysteine Materials. Restriction enzymes and other molecular biology reagents were obtained from Promega (Madison, WI), Roche (Indianapolis, IN), or New proteases cleave specific substrates within a cell, resulting in a con- England Biolabs (Beverly, MA). Horseradish peroxidase-conjugated antibod- served series of biochemical and morphological changes (5). At least ies and enhanced chemiluminescence reagents were purchased from Amer- sham Pharmacia Biotech (Piscataway, NJ). TA and RU486 were purchased Received 8/1/02; accepted 10/31/02. from Sigma Chemical Company (St. Louis, MO). All tissue culture media and The costs of publication of this article were defrayed in part by the payment of page supplements were from Invitrogen (Carlsbad, CA). The caspase inhibitors, charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Z-LEHD-FMK and Z-DQMD-FMK, and the negative control, Z-FA-FMK, 1 Supported by NIH Research Grant AI/HL40976 (to G. L.), ALA Grant RG-034N (to were purchased from Enzyme Systems Products (Livermore, CA). All other N. M. R.), and NIH Training Grant 5T32 DK07705 (to S. L. P.). chemicals were purchased from Fisher Scientific (Pittsburgh, PA). 2 These two authors contributed equally to this work. Cell Culture and Stable Transfections. Cells (697) are a cloned human 3 To whom requests for reprints should be addressed, at Thomas Jefferson University, 233 South 10th Street, BLSB #350, Philadelphia, PA 19107. Phone: (215) 503-4634; Fax: pre-B leukemic cell line derived from childhood acute lymphoblastic leukemia, (215) 503-5393; E-mail: [email protected]. which carries the t(1;19) translocation. All cell lines were cultured with RPMI 4 The abbreviations used are: GC, glucocorticoid; GR, glucocorticoid receptor; TA, media supplemented with 10% fetal bovine serum, 2 mML-glutamine, (100 triamcinolone acetonide; DN, dominant negative; MAPK, mitogen-activated protein ki- nase; MKP-1, MAPK phosphatase-1; GRE, glucocorticoid response element; TNF, tumor necrosis factor; JNK, c-Jun N-terminal kinase; mAb, monoclonal antibody; RT-PCR, 5 S. L. Planey, A. Derfoul, A. Steplewski, N. M. Robertson, and G. Litwack. Inhibition reverse transcription-PCR; GST, glutathione S-transferase; TRAIL, TNF-related apopto- of glucocorticoid-induced apoptosis in 697 pre-B lymphocytes by the mineralocorticoid sis-inducing ligand; GAPDH, glyceraldehydes-3-phosphate dehydrogenase. receptor N-terminal domain, submitted for publication. 172 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2003 American Association for Cancer Research. GC-INDUCED APOPTOSIS IN PRE-B LEUKEMIC CELLS ␮ units/ml), and streptomycin (100 g/ml) at 37°C under 5% CO2. Exponentially One-Step RT-PCR Master Mix reagents (Applied Biosystems, Foster City, growing cells were used throughout all experiments at a concentration of CA). The 18S rRNA control primer/probe set was purchased from Applied 5 ϫ 105-1 ϫ 106 cells/ml. Biosystems, and the MKP-1 primer/probe set was purchased form Midland Mammalian expression vectors were constructed as described previously Certified Reagents (Midland, TX). The sequence of the 6-carboxyfluorescein- (16, 17). The cell lines 697-Neo and 697-CrmA, 697-Bcl-2, 697-DN- labeled MKP-1 probe is 5Ј-6FAM-CCCGGTCAGCCACCATCTGCC- caspase-8, 697-DN-caspase-9, and 697-DN-caspase-10 were generated by TAMRA. The MKP-1 primer sequences are 5Ј-CACTGCCAGCAGCATT-3Ј resuspending 1 ϫ 107 cells in serum-free RPMI containing 10 ␮gofthe and 5Ј-CTCGATTAGTCCTCATAAGGTAAGCA-3Ј. Reactions were per- expression plasmids: pcDNA3.0/Neo; pcDNA3.0/CrmA; pcDNA3.0/Bcl-2; formed in duplicate in an ABI Prism 7900 Sequence Detection System using pcDNA3.0/DN-caspase-8; pcDNA3.0/DN-caspase-9; or pcDNA3.0/DN- the recommended cycling conditions. Data were analyzed using ABI SDS caspase-10. The cells were electroporated using a 4-mm gap cuvette at 0.22kV, software. Threshold cycle (Ct) values were determined by the software as 500 microfarads, and 27–31 ms. Cells were cultured for 18–48 h before the described previously (20). Gene expression of treated cells relative to control addition of G418 at 1 mg/ml. After selection for 4 weeks, cells were subcloned cells was quantitated using 2Ct of treated cells Ϫ Ct of control cells. In Fig. 5C, the by limiting dilution and screened by immunoblot analysis for protein expres- expression of MKP-1 in vehicle-treated cells is normalized to a value of 1. sion using an ␣-T7 mouse mAb (Novagen, Madison, WI) against the T7 JNK Activity Assay. To determine JNK activity, cells were lysed in buffer epitope tag within the expression plasmid. containing 20 mM HEPES (pH 7.5), 75 mM NaCl, 2.5 mM MgCl2, 0.1 mM Determination of Cell Number, Viability, and Caspase Activity.
Load more

Recommended publications
  • Plant Mitogen-Activated Protein Kinase Signaling Cascades Guillaume Tena*, Tsuneaki Asai†, Wan-Ling Chiu‡ and Jen Sheen§
    392 Plant mitogen-activated protein kinase signaling cascades Guillaume Tena*, Tsuneaki Asai†, Wan-Ling Chiu‡ and Jen Sheen§ Mitogen-activated protein kinase (MAPK) cascades have components that link sensors/receptors to target genes emerged as a universal signal transduction mechanism that and other cellular responses. connects diverse receptors/sensors to cellular and nuclear responses in eukaryotes. Recent studies in plants indicate that In the past few years, it has become apparent that mitogen- MAPK cascades are vital to fundamental physiological functions activated protein kinase (MAPK) cascades play some of the involved in hormonal responses, cell cycle regulation, abiotic most essential roles in plant signal transduction pathways stress signaling, and defense mechanisms. New findings have from cell division to cell death (Figure 1). MAPK cascades revealed the complexity and redundancy of the signaling are evolutionarily conserved signaling modules with essen- components, the antagonistic nature of distinct pathways, and tial regulatory functions in eukaryotes, including yeasts, the use of both positive and negative regulatory mechanisms. worms, flies, frogs, mammals and plants. The recent enthu- siasm for plant MAPK cascades is backed by numerous Addresses studies showing that plant MAPKs are activated by hor- Department of Molecular Biology, Massachusetts General Hospital, mones, abiotic stresses, pathogens and pathogen-derived Department of Genetics, Harvard Medical School, Wellman 11, elicitors, and are also activated at specific stages during the 50 Blossom Street, Boston, Massachusetts 02114, USA cell cycle [2]. Until recently, studies of MAPK cascades in *e-mail: [email protected] †e-mail: [email protected] plants were focused on cDNA cloning [3,4] and used a ‡e-mail: [email protected] MAPK in-gel assay, MAPK and tyrosine-phosphate anti- §e-mail: [email protected] bodies, and kinase inhibitors to connect signals to MAPKs Current Opinion in Plant Biology 2001, 4:392–400 [2].
    [Show full text]
  • ERK Cascade Pathway
    Biochemistry and Biophysics Reports 7 (2016) 10–19 Contents lists available at ScienceDirect Biochemistry and Biophysics Reports journal homepage: www.elsevier.com/locate/bbrep Glutamine up-regulates MAPK phosphatase-1 induction via activation of Ca2 þ- ERK cascade pathway Otgonzaya Ayush a, Zhe Wu Jin c, Hae-Kyoung Kim b, Yu-Rim Shin d, Suhn-Young Im e, Hern-Ku Lee b,n a Department of Dermatology, Medical University, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia b Departments of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Republic of Korea c Department of Anatomy and Histology and Embryology, Yanbian University Medical College, YanJi City, Jilin Province, China d Biofoods Story, Inc, 477 Jeonjucheon-seoro, Wansan-gu, Jeonju, Jeonbuk 560-821, Republic of Korea e Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, Republic of Korea article info abstract Article history: The non-essential amino acid L-glutamine (Gln) displays potent anti-inflammatory activity by deacti- Received 3 February 2016 vating p38 mitogen activating protein kinase and cytosolic phospholipase A2 via induction of MAPK Received in revised form phosphatase-1 (MKP-1) in an extracellular signal-regulated kinase (ERK)-dependent way. In this study, 9 May 2016 the mechanism of Gln-mediated ERK-dependency in MKP-1 induction was investigated. Gln increased Accepted 11 May 2016 ERK phosphorylation and activity, and phosphorylations of Ras, c-Raf, and MEK, located in the upstream Available online 12 May 2016 pathway of ERK, in response to lipopolysaccharidein vitro and in vivo. Gln-induced dose-dependent 2 þ Keywords: transient increases in intracellular calcium ([Ca ]i) in MHS macrophage cells.
    [Show full text]
  • Lipopolysaccharide Macrophage Responses to Tristetraprolin
    Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide This information is current as of August 28, 2019. Tim Smallie, Ewan A. Ross, Alaina J. Ammit, Helen E. Cunliffe, Tina Tang, Dalya R. Rosner, Michael L. Ridley, Downloaded from Christopher D. Buckley, Jeremy Saklatvala, Jonathan L. Dean and Andrew R. Clark J Immunol 2015; 195:277-288; Prepublished online 27 May 2015; http://www.jimmunol.org/ doi: 10.4049/jimmunol.1402830 http://www.jimmunol.org/content/195/1/277 Supplementary http://www.jimmunol.org/content/suppl/2015/05/27/jimmunol.140283 Material 0.DCSupplemental at Aston Univ - SciTech Faculty Team on August 28, 2019 References This article cites 65 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/195/1/277.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 The Authors All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide Tim Smallie,*,1 Ewan A.
    [Show full text]
  • Dual-Specificity Phosphatases in Immunity and Infection
    International Journal of Molecular Sciences Review Dual-Specificity Phosphatases in Immunity and Infection: An Update Roland Lang * and Faizal A.M. Raffi Institute of Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany * Correspondence: [email protected]; Tel.: +49-9131-85-22979 Received: 15 May 2019; Accepted: 30 May 2019; Published: 2 June 2019 Abstract: Kinase activation and phosphorylation cascades are key to initiate immune cell activation in response to recognition of antigen and sensing of microbial danger. However, for balanced and controlled immune responses, the intensity and duration of phospho-signaling has to be regulated. The dual-specificity phosphatase (DUSP) gene family has many members that are differentially expressed in resting and activated immune cells. Here, we review the progress made in the field of DUSP gene function in regulation of the immune system during the last decade. Studies in knockout mice have confirmed the essential functions of several DUSP-MAPK phosphatases (DUSP-MKP) in controlling inflammatory and anti-microbial immune responses and support the concept that individual DUSP-MKP shape and determine the outcome of innate immune responses due to context-dependent expression and selective inhibition of different mitogen-activated protein kinases (MAPK). In addition to the canonical DUSP-MKP, several small-size atypical DUSP proteins regulate immune cells and are therefore also reviewed here. Unexpected and complex findings in DUSP knockout mice pose new questions regarding cell type-specific and redundant functions. Another emerging question concerns the interaction of DUSP-MKP with non-MAPK binding partners and substrate proteins.
    [Show full text]
  • Roles of Induced Expression of MAPK Phosphatase-2 in Tumor Development in RET-MEN2A Transgenic Mice
    Oncogene (2008) 27, 5684–5695 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc ORIGINAL ARTICLE Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice T Hasegawa1,2, A Enomoto1,3, T Kato1, K Kawai1, R Miyamoto1, M Jijiwa1, M Ichihara4, M Ishida1, N Asai1, YMurakumo 1, K Ohara1,2, YNiwa 2, H Goto2 and M Takahashi1,5 1Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 2Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 3Institute for Advanced Research, Nagoya University, Nagoya, Japan; 4Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan and 5Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan Germline mutations in the RET tyrosine kinase gene are line-derived neurotrophic factor (GDNF) family responsible for the development of multiple endocrine of ligands (GFLs). It has a crucial role in transducing neoplasia 2A and 2B (MEN2A and MEN2B). However, growth and differentiation signals in tissues knowledge of the fundamental principles that determine derived from the neural crest and the developing kidney the mutant RET-mediated signaling remains elusive. (Schuchardt et al., 1994; Moore et al., 1996; Pichel Here, we report increased expression of mitogen-activated et al., 1996; Sa´ nchez et al., 1996; Treanor et al., 1996; protein kinase phosphatase-2 (MKP-2) in carcinomas Rosenthal, 1999; Airaksinen and Saarma, 2002). developed in transgenic mice carrying RET with the It has been firmly established that germline mutations MEN2A mutation (RET-MEN2A).
    [Show full text]
  • Dual-Specificity Phosphatases 2
    Genes and Immunity (2013) 14, 1–6 & 2013 Macmillan Publishers Limited All rights reserved 1466-4879/13 www.nature.com/gene REVIEW Dual-specificity phosphatases 2: surprising positive effect at the molecular level and a potential biomarker of diseases WWei1,2, Y Jiao2,3, A Postlethwaite4,5, JM Stuart4,5, Y Wang6, D Sun1 and W Gu2 Dual-specificity phosphatases (DUSPs) is an emerging subclass of the protein tyrosine phosphatase gene superfamily, a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/ phosphothreonine residues within the one substrate. Recently, a series of investigations of DUSPs defined their essential roles in cell proliferation, cancer and the immune response. This review will focus on DUSP2, its involvement in different diseases and its potential as a therapeutic target. Genes and Immunity (2013) 14, 1–6; doi:10.1038/gene.2012.54; published online 29 November 2012 Keywords: dual-specificity phosphatases; disease; mitogen-activated protein kinase; immune INTRODUCTION extracellular stimuli. Inducible nucleuses MKPs include DUSP1, Mitogen-activated protein kinase (MAPK) activation cascades DUSP2, DUSP4 and DUSP5, which originated from a common mediate various physiological processes, such as cell proliferation, ancestral gene. They were shown to dephosphorylate Erks, Jnk differentiation, stress responses, inflammation, apoptosis and and p38 MAPKs to the same extent and to be induced by growth immune defense.1–4 Dysregulation of MAPK activation cascades or stress signals. DUSP6, DUSP7 and DUSP9 are cytoplasmic Erk- has been implicated in various diseases and has been the focus of specific MPKs, which can preferentially recognize Erk1 and Erk2 extensive research.5–7 MAPKs are grouped into three major classes in vitro.
    [Show full text]
  • Kinase Signaling Cascades in the Mitochondrion: a Matter of Life Or Death$
    Free Radical Biology & Medicine 38 (2005) 2–11 www.elsevier.com/locate/freeradbiomed Serial Review: The powerhouse takes control of the cell: The role of mitochondria in signal transduction Serial Review Editor: Victor Darley-Usmar Kinase signaling cascades in the mitochondrion: a matter of life or death$ Craig Horbinski, Charleen T. Chu* Division of Neuropathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Received 15 July 2004; accepted 22 September 2004 Available online 27 October 2004 Abstract In addition to powering energy needs of the cell, mitochondria function as pivotal integrators of cell survival/death signals. In recent years, numerous studies indicate that each of the major kinase signaling pathways can be stimulated to target the mitochondrion. These include protein kinase A, protein kinase B/Akt, protein kinase C, extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen- activated protein kinase. Although most studies focus on phosphorylation of pro- and antiapoptotic proteins (BAD, Bax, Bcl-2, Bcl-xL), kinase- mediated regulation of complex I activity, anion and cation channels, metabolic enzymes, and Mn-SOD mRNA has also been reported. Recent identification of a number of scaffold proteins (AKAP, PICK, Sab) that bring specific kinases to the cytoplasmic surface of mitochondria further emphasizes the importance of mitochondrial kinase signaling. Immunogold electron microscopy, subcellular fractionation, and immuno- fluorescence studies demonstrate the presence of kinases within subcompartments of the mitochondrion, following diverse stimuli and in neurodegenerative diseases. Given the sensitivity of these signaling pathways to reactive oxygen and nitrogen species, in situ activation of mitochondrial kinases may represent a potent reverse-signaling mechanism for communication of mitochondrial status to the rest of the cell.
    [Show full text]
  • The Dual-Specificity Phosphatase 10 (DUSP10)
    International Journal of Molecular Sciences Review The Dual-Specificity Phosphatase 10 (DUSP10): Its Role in Cancer, Inflammation, and Immunity Marta Jiménez-Martínez 1,2,3, Konstantinos Stamatakis 1,2,3 and Manuel Fresno 1,2,3,* 1 Department of Cell Biology and Immunology, Centro de Biología Molecular ‘Severo Ochoa’ (CSIC-UAM), 28049 Madrid, Spain; [email protected] (M.J.-M.); [email protected] (K.S.) 2 Department of Molecular Biology, Universidad Autónoma de Madrid, 28049 Madrid, Spain 3 Instituto de Investigación Sanitaria la Princesa (IIS-P), 28006 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-911-964-565 Received: 13 February 2019; Accepted: 30 March 2019; Published: 1 April 2019 Abstract: Cancer is one of the most diagnosed diseases in developed countries. Inflammation is a common response to different stress situations including cancer and infection. In those processes, the family of mitogen-activated protein kinases (MAPKs) has an important role regulating cytokine secretion, proliferation, survival, and apoptosis, among others. MAPKs regulate a large number of extracellular signals upon a variety of physiological as well as pathological conditions. MAPKs activation is tightly regulated by phosphorylation/dephosphorylation events. In this regard, the dual-specificity phosphatase 10 (DUSP10) has been described as a MAPK phosphatase that negatively regulates p38 MAPK and c-Jun N-terminal kinase (JNK) in several cellular types and tissues. Several studies have proposed that extracellular signal-regulated kinase (ERK) can be also modulated by DUSP10. This suggests a complex role of DUSP10 on MAPKs regulation and, in consequence, its impact in a wide variety of responses involved in both cancer and inflammation.
    [Show full text]
  • The P38 MAPK Pathway in Rheumatoid Arthritis: a Sideways Look Andrew R
    The Open Rheumatology Journal, 2012, 6, (Suppl 2: M2) 209-219 209 Open Access The p38 MAPK Pathway in Rheumatoid Arthritis: A Sideways Look Andrew R. Clark* and Jonathan L.E. Dean Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Road, Hammersmith, London W6 8LH, UK Abstract: The p38 mitogen-activated protein kinase (MAPK) signaling pathway has been strongly implicated in many of the processes that underlie the pathology of rheumatoid arthritis (RA). For many years it has been considered a promising target for development of new anti-inflammatory drugs with which to treat RA and other chronic immune-mediated inflammatory diseases. However, several recent clinical trials have concluded in a disappointing manner. Why is this so, if p38 MAPK clearly contributes to the excessive production of inflammatory mediators, the destruction of bone and cartilage? We argue that, to explain the apparent failure of p38 inhibitors in the rheumatology clinic, we need to understand better the complexities of the p38 pathway and its many levels of communication with other cellular signaling pathways. In this review we look at the p38 MAPK pathway from a slightly different perspective, emphasising its role in post-transcriptional rather than transcriptional control of gene expression, and its contribution to the off-phase rather than the on-phase of the inflammatory response. Keywords: p38 MAPK, inflammatory mediators, gene expression, phosphorylation, listeria monocytogenes. ACTIVATION OF P38 MAPK play a major role in the transmission of activating signals from cell surface receptors to TAK1 [4-8]. In mammals four members of the p38 MAPK family are encoded by discrete genes.
    [Show full text]
  • Type 2 Cgmp-Dependent Protein Kinase Regulates Homeostasis by Blocking C-Jun N-Terminal Kinase in the Colon Epithelium
    Cell Death and Differentiation (2014) 21, 427–437 & 2014 Macmillan Publishers Limited All rights reserved 1350-9047/14 www.nature.com/cdd Type 2 cGMP-dependent protein kinase regulates homeostasis by blocking c-Jun N-terminal kinase in the colon epithelium R Wang1, I-K Kwon1, N Singh1, B Islam1, K Liu1, S Sridhar2, F Hofmann3 and DD Browning*,1 Analysis of knockout animals indicates that 30,50cyclic guanosine monophosphate (cGMP) has an important role in gut homeostasis but the signaling mechanism is not known. The goals of this study were to test whether increasing cGMP could affect colon homeostasis and determine the mechanism. We increased cGMP in the gut of Prkg2 þ / þ and Prkg2 À / À mice by treating with the PDE5 inhibitor Vardenafil (IP). Proliferation, differentiation and apoptosis in the colon mucosa were then quantitated. Vardenafil (Vard) treatment increased cGMP in colon mucosa of all mice, but reduced proliferation and apoptosis, and increased differentiation only in Prkg2 þ / þ mice. Vard and cGMP treatment also increased dual specificity protein phosphatase 10 (DUSP10) expression and reduced phospho-c-Jun N-terminal kinase (JNK) levels in the colon mucosa of Prkg2 þ / þ but not Prkg2 À / À mice. Treatment of Prkg2 À / À mice with the JNK inhibitor SP600125 reversed the defective homeostasis observed in these animals. Activation of protein kinase G2 (PKG2) in goblet-like LS174T cells increased DUSP10 expression and reduced JNK activity. PKG2 also increased goblet cell-specific MUC2 expression in LS174T cells, and this process was blocked by DUSP10-specific siRNA. The ability of cGMP signaling to inhibit JNK-induced apoptosis in vivo was demonstrated using dextran sodium sulfate (DSS) to stress the colon epithelium.
    [Show full text]
  • Dual Specificity Phosphatases from Molecular Mechanisms to Biological Function
    International Journal of Molecular Sciences Dual Specificity Phosphatases From Molecular Mechanisms to Biological Function Edited by Rafael Pulido and Roland Lang Printed Edition of the Special Issue Published in International Journal of Molecular Sciences www.mdpi.com/journal/ijms Dual Specificity Phosphatases Dual Specificity Phosphatases From Molecular Mechanisms to Biological Function Special Issue Editors Rafael Pulido Roland Lang MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Rafael Pulido Roland Lang Biocruces Health Research Institute University Hospital Erlangen Spain Germany Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal International Journal of Molecular Sciences (ISSN 1422-0067) from 2018 to 2019 (available at: https: //www.mdpi.com/journal/ijms/special issues/DUSPs). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03921-688-8 (Pbk) ISBN 978-3-03921-689-5 (PDF) c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editors ....................................
    [Show full text]
  • Revisiting the Roles of VHR/DUSP3 Phosphatase in Human Diseases
    REVIEW ARTICLE Revisiting the roles of VHR/DUSP3 phosphatase in human diseases Lilian Cristina Russo, Je´ssica Oliveira Farias, Pault Yeison Minaya Ferruzo, Lucas Falca˜o Monteiro, Fa´bio Luı´sForti* Departamento de Bioquı´mica, Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo, SP, BR. Russo LC, Farias JO, Ferruzo PY,Monteiro LF,Forti FL. Revisiting the roles of VHR/DUSP3 phosphatase in human diseases. Clinics. 2018;73(suppl 1):e466s *Corresponding author. E-mail: fl[email protected] Protein tyrosine phosphatases have long been considered key regulators of biological processes and are there- fore implicated in the origins of various human diseases. Heterozygosity, mutations, deletions, and the complete loss of some of these enzymes have been reported to cause neurodegenerative diseases, autoimmune syndromes, genetic disorders, metabolic diseases, cancers, and many other physiological imbalances. Vaccinia H1-related phos- phatase, also known as dual-specificity phosphatase 3, is a protein tyrosine phosphatase enzyme that regulates the phosphorylation of the mitogen-activated protein kinase signaling pathway, a central mediator of a diver- sity of biological responses. It has been suggested that vaccinia H1-related phosphatase can act as a tumor sup- pressor or tumor-promoting phosphatase in different cancers. Furthermore, emerging evidence suggests that this enzyme has many other biological functions, such as roles in immune responses, thrombosis, hemostasis, angio- genesis, and genomic stability, and this broad spectrum of vaccinia H1-related phosphatase activity is likely the result of its diversity of substrates. Hence, fully identifying and characterizing these substrate-phosphatase interactions will facilitate the identification of pharmacological inhibitors of vaccinia H1-related phosphatase that can be evaluated in clinical trials.
    [Show full text]