DUSP10/MKP5 Antibody A
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Deciphering the Functions of Ets2, Pten and P53 in Stromal Fibroblasts in Multiple
Deciphering the Functions of Ets2, Pten and p53 in Stromal Fibroblasts in Multiple Breast Cancer Models DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Julie Wallace Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2013 Dissertation Committee: Michael C. Ostrowski, PhD, Advisor Gustavo Leone, PhD Denis Guttridge, PhD Dawn Chandler, PhD Copyright by Julie Wallace 2013 Abstract Breast cancer is the second most common cancer in American women, and is also the second leading cause of cancer death in women. It is estimated that nearly a quarter of a million new cases of invasive breast cancer will be diagnosed in women in the United States this year, and approximately 40,000 of these women will die from breast cancer. Although death rates have been on the decline for the past decade, there is still much we need to learn about this disease to improve prevention, detection and treatment strategies. The majority of early studies have focused on the malignant tumor cells themselves, and much has been learned concerning mutations, amplifications and other genetic and epigenetic alterations of these cells. However more recent work has acknowledged the strong influence of tumor stroma on the initiation, progression and recurrence of cancer. Under normal conditions this stroma has been shown to have protective effects against tumorigenesis, however the transformation of tumor cells manipulates this surrounding environment to actually promote malignancy. Fibroblasts in particular make up a significant portion of this stroma, and have been shown to impact various aspects of tumor cell biology. -
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
DUSP10 Regulates Intestinal Epithelial Cell Growth and Colorectal Tumorigenesis
Oncogene (2016) 35, 206–217 © 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16 www.nature.com/onc ORIGINAL ARTICLE DUSP10 regulates intestinal epithelial cell growth and colorectal tumorigenesis CW Png1,2, M Weerasooriya1,2, J Guo3, SJ James1,2,HMPoh1,2, M Osato3, RA Flavell4, C Dong5, H Yang3 and Y Zhang1,2 Dual specificity phosphatase 10 (DUSP10), also known as MAP kinase phosphatase 5 (MKP5), negatively regulates the activation of MAP kinases. Genetic polymorphisms and aberrant expression of this gene are associated with colorectal cancer (CRC) in humans. However, the role of DUSP10 in intestinal epithelial tumorigenesis is not clear. Here, we showed that DUSP10 knockout (KO) mice had increased intestinal epithelial cell (IEC) proliferation and migration and developed less severe colitis than wild-type (WT) mice in response to dextran sodium sulphate (DSS) treatment, which is associated with increased ERK1/2 activation and Krüppel-like factor 5 (KLF5) expression in IEC. In line with increased IEC proliferation, DUSP10 KO mice developed more colon tumours with increased severity compared with WT mice in response to administration of DSS and azoxymethane (AOM). Furthermore, survival analysis of CRC patients demonstrated that high DUSP10 expression in tumours was associated with significant improvement in survival probability. Overexpression of DUSP10 in Caco-2 and RCM-1 cells inhibited cell proliferation. Our study showed that DUSP10 negatively regulates IEC growth and acts as a suppressor for CRC. Therefore, it could be targeted for the development of therapies for colitis and CRC. Oncogene (2016) 35, 206–217; doi:10.1038/onc.2015.74; published online 16 March 2015 INTRODUCTION development. -
Molecular Programming of Tumor-Infiltrating CD8 T Cells and IL15 Resistance
Published OnlineFirst August 2, 2016; DOI: 10.1158/2326-6066.CIR-15-0178 Research Article Cancer Immunology Research Molecular Programming of Tumor-Infiltrating CD8þ T Cells and IL15 Resistance Andrew L. Doedens1, Mark P. Rubinstein1,2, Emilie T. Gross3, J. Adam Best1, David H. Craig2, Megan K. Baker2, David J. Cole2, Jack D. Bui3, and Ananda W. Goldrath1 Abstract Despite clinical potential and recent advances, durable immu- in the lung and spleen were activated and dramatically expanded. þ notherapeutic ablation of solid tumors is not routinely achieved. Tumor-infiltrating CD8 T cells exhibited cell-extrinsic and cell- IL15expandsnaturalkillercell(NK),naturalkillerTcell(NKT)and intrinsic resistance to IL15. Our data showed that in the case of þ CD8 T-cell numbers and engages the cytotoxic program, and thus persistent viral or tumor antigen, single-agent systemic IL15cx is under evaluation for potentiation of cancer immunotherapy. We treatment primarily expanded antigen-irrelevant or extratumoral þ found that short-term therapy with IL15 bound to soluble IL15 CD8 Tcells.Weidentified exhaustion, tissue-resident memory, þ receptor a–Fc (IL15cx; a form of IL15 with increased half-life and and tumor-specific molecules expressed in tumor-infiltrating CD8 activity) was ineffective in the treatment of autochthonous PyMT T cells, which may allow therapeutic targeting or programming þ murine mammary tumors, despite abundant CD8 T-cell infiltra- of specific subsets to evade loss of function and cytokine resist- tion. Probing of this poor responsiveness revealed that IL15cx ance, and, in turn, increase the efficacy of IL2/15 adjuvant cytokine þ only weakly activated intratumoral CD8 T cells, even though cells therapy. -
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. -
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. -
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. -
Lipid Phosphatases Identified by Screening a Mouse Phosphatase Shrna Library Regulate T-Cell Differentiation and Protein Kinase
Lipid phosphatases identified by screening a mouse PNAS PLUS phosphatase shRNA library regulate T-cell differentiation and Protein kinase B AKT signaling Liying Guoa, Craig Martensb, Daniel Brunob, Stephen F. Porcellab, Hidehiro Yamanea, Stephane M. Caucheteuxa, Jinfang Zhuc, and William E. Paula,1 aCytokine Biology Unit, cMolecular and Cellular Immunoregulation Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and bGenomics Unit, Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840 Contributed by William E. Paul, March 27, 2013 (sent for review December 18, 2012) Screening a complete mouse phosphatase lentiviral shRNA library production (10, 11). Conversely, constitutive expression of active using high-throughput sequencing revealed several phosphatases AKT leads to increased proliferation and enhanced Th1/Th2 cy- that regulate CD4 T-cell differentiation. We concentrated on two lipid tokine production (12). phosphatases, the myotubularin-related protein (MTMR)9 and -7. The amount of PI[3,4,5]P3 and the level of AKT activation are Silencing MTMR9 by shRNA or siRNA resulted in enhanced T-helper tightly controlled by several mechanisms, including breakdown of (Th)1 differentiation and increased Th1 protein kinase B (PKB)/AKT PI[3,4,5]P3, down-regulation of the amount and activity of PI3K, phosphorylation while silencing MTMR7 caused increased Th2 and and the dephosphorylation of AKT (13). PTEN is a major negative Th17 differentiation and increased AKT phosphorylation in these regulator of PI[3,4,5]P3. It removes the 3-phosphate from the cells. -
Molecular Alterations and Tumor Suppressive Function of the DUSP22 (Dual Specificity Phosphatase 22) Gene in Peripheral T-Cell Lymphoma Subtypes
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 42 Research Paper Molecular alterations and tumor suppressive function of the DUSP22 (Dual Specificity Phosphatase 22) gene in peripheral T-cell lymphoma subtypes Pierre Mélard1,2,*, Yamina Idrissi1,* Laetitia Andrique1,3, Sandrine Poglio1, Martina Prochazkova-Carlotti1, Sabine Berhouet3, Cécile Boucher3, Elodie Laharanne1,3, Edith Chevret1, Anne Pham-Ledard1,4, Andréa Carla De Souza Góes1,5, Véronique Guyonnet-Duperat6, Alice Bibeyran6, François Moreau-Gaudry6,7, Béatrice Vergier1,2, Marie Beylot-Barry1,4, Jean-Philippe Merlio1,3, David Cappellen1,3 1Institut National de la Santé et de la Recherche Médicale (Inserm) U1053, Universitaire de Bordeaux, F-33076 Bordeaux, France 2Service de Pathologie, Centre Hospitalier Universitaire de Bordeaux, Hôpital Haut-Lévêque, F-33604 Pessac, France 3Service de Biologie des Tumeurs-Tumorothèque, Centre Hospitalier Universitaire de Bordeaux, Hôpital Haut-Lévêque, F-33604 Pessac, France 4Service de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, F-33000 Bordeaux, France 5Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, CEP 20550-013 Rio de Janeiro, Brazil 6Plateforme de Vectorologie, Unité Mixte de Services (UMS TBM-Core), Centre National de la Recherche Scientifique (CNRS)- Institut National de la Santé et de la Recherche Médicale (Inserm)-Universitaire de Bordeaux, F-33076 Bordeaux, France 7Biothérapies des Maladies Génétiques et Cancers, Institut National de la Santé -
Dysfunction of Poly
Published OnlineFirst May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-1037 Cancer Molecular Cell Biology Research Dysfunction of Poly (ADP-Ribose) Glycohydrolase Induces a Synthetic Lethal Effect in Dual Specificity Phosphatase 22-Deficient Lung Cancer Cells Yuka Sasaki1,2, Hiroaki Fujimori1,2, Miyuki Hozumi2,3,Takae Onodera1,2,Tadashige Nozaki1,4, Yasufumi Murakami3, Kazuto Ashizawa5, Kengo Inoue6, Fumiaki Koizumi7, and Mitsuko Masutani1,2 Abstract Poly (ADP-ribose) glycohydrolase (PARG) is the main cancer A549, PC14, and SBC5 cells, and inhibited the enzyme responsible for catabolism of poly (ADP-ribose) PI3K/AKT/mTOR pathway in A549 cells, suggesting that (PAR), synthesized by PARP. PARG dysfunction sensitizes dual depletion of PARG and DUSP22 induced apoptosis by certain cancer cells to alkylating agents and cisplatin by upregulating PUMA and suppressing the PI3K/AKT/mTOR perturbing the DNA damage response. The gene mutations pathway. Consistently, the growth of tumors derived from that sensitize cancer cells to PARG dysfunction-induced death double knockdown A549 cells was slower compared with remain to be identified. Here, we performed a comprehensive those derived from control siRNA-transfected cells. Taken analysis of synthetic lethal genes using inducible PARG together, these results indicate that DUSP22 deficiency knockdown cells and identified dual specificity phosphatase exerts a synthetic lethal effect when combined with PARG 22 (DUSP22) as a novel synthetic lethal gene related to PARG dysfunction, suggesting that DUSP22 dysfunction could dysfunction. DUSP22 is considered a tumor suppressor and its be a useful biomarker for cancer therapy using PARG mutation has been frequently reported in lung, colon, and inhibitors. other tumors. -
Dual-Specificity Phosphatase 3 Deletion Promotes Obesity, Non
www.nature.com/scientificreports OPEN Dual‑specifcity phosphatase 3 deletion promotes obesity, non‑alcoholic steatohepatitis and hepatocellular carcinoma Sophie Jacques1,10, Arash Arjomand1,10, Hélène Perée1, Patrick Collins2, Alice Mayer3, Arnaud Lavergne3, Marie Wéry1, Myriam Mni1, Alexandre Hego4, Virginie Thuillier1, Guillaume Becker5, Mohamed Ali Bahri5, Alain Plenevaux5, Emmanuel Di Valentin6, Cécile Oury7, Michel Moutschen8, Philippe Delvenne2, Nicolas Paquot9 & Souad Rahmouni1* Non‑alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic pathology in Western countries. It encompasses a spectrum of conditions ranging from simple steatosis to more severe and progressive non‑alcoholic steatohepatitis (NASH) that can lead to hepatocellular carcinoma (HCC). Obesity and related metabolic syndrome are important risk factors for the development of NAFLD, NASH and HCC. DUSP3 is a small dual‑specifcity protein phosphatase with a poorly known physiological function. We investigated its role in metabolic syndrome manifestations and in HCC using a mouse knockout (KO) model. While aging, DUSP3‑KO mice became obese, exhibited insulin resistance, NAFLD and associated liver damage. These phenotypes were exacerbated under high fat diet (HFD). In addition, DEN administration combined to HFD led to rapid HCC development in DUSP3‑KO compared to wild type (WT) mice. DUSP3‑KO mice had more serum triglycerides, cholesterol, AST and ALT compared to control WT mice under both regular chow diet (CD) and HFD. The level of fasting insulin was higher compared to WT mice, though, fasting glucose as well as glucose tolerance were normal. At the molecular level, HFD led to decreased expression of DUSP3 in WT mice. DUSP3 deletion was associated with increased and consistent phosphorylation of the insulin receptor (IR) and with higher activation of the downstream signaling pathway. -
Live-Cell Imaging Rnai Screen Identifies PP2A–B55α and Importin-Β1 As Key Mitotic Exit Regulators in Human Cells
LETTERS Live-cell imaging RNAi screen identifies PP2A–B55α and importin-β1 as key mitotic exit regulators in human cells Michael H. A. Schmitz1,2,3, Michael Held1,2, Veerle Janssens4, James R. A. Hutchins5, Otto Hudecz6, Elitsa Ivanova4, Jozef Goris4, Laura Trinkle-Mulcahy7, Angus I. Lamond8, Ina Poser9, Anthony A. Hyman9, Karl Mechtler5,6, Jan-Michael Peters5 and Daniel W. Gerlich1,2,10 When vertebrate cells exit mitosis various cellular structures can contribute to Cdk1 substrate dephosphorylation during vertebrate are re-organized to build functional interphase cells1. This mitotic exit, whereas Ca2+-triggered mitotic exit in cytostatic-factor- depends on Cdk1 (cyclin dependent kinase 1) inactivation arrested egg extracts depends on calcineurin12,13. Early genetic studies in and subsequent dephosphorylation of its substrates2–4. Drosophila melanogaster 14,15 and Aspergillus nidulans16 reported defects Members of the protein phosphatase 1 and 2A (PP1 and in late mitosis of PP1 and PP2A mutants. However, the assays used in PP2A) families can dephosphorylate Cdk1 substrates in these studies were not specific for mitotic exit because they scored pro- biochemical extracts during mitotic exit5,6, but how this relates metaphase arrest or anaphase chromosome bridges, which can result to postmitotic reassembly of interphase structures in intact from defects in early mitosis. cells is not known. Here, we use a live-cell imaging assay and Intracellular targeting of Ser/Thr phosphatase complexes to specific RNAi knockdown to screen a genome-wide library of protein substrates is mediated by a diverse range of regulatory and targeting phosphatases for mitotic exit functions in human cells. We subunits that associate with a small group of catalytic subunits3,4,17.