PTPN6 Sirna Set I PTPN6 Sirna Set I

Total Page:16

File Type:pdf, Size:1020Kb

PTPN6 Sirna Set I PTPN6 Sirna Set I Catalog # Aliquot Size P33-911-05 3 x 5 nmol P33-911-20 3 x 20 nmol P33-911-50 3 x 50 nmol PTPN6 siRNA Set I siRNA duplexes targeted against three exon regions Catalog # P33-911 Lot # Z2085-25 Specificity Formulation PTPN6 siRNAs are designed to specifically knock-down The siRNAs are supplied as a lyophilized powder and human PTPN6 expression. shipped at room temperature. Product Description Reconstitution Protocol PTPN6 siRNA is a pool of three individual synthetic siRNA Briefly centrifuge the tubes (maximum RCF 4,000g) to duplexes designed to knock-down human PTPN6 mRNA collect lyophilized siRNA at the bottom of the tube. expression. Each siRNA is 19-25 bases in length. The gene Resuspend the siRNA in 50 µl of DEPC-treated water accession number is NM_080548. (supplied by researcher), which results in a 1x stock solution (10 µM). Gently pipet the solution 3-5 times to mix Gene Aliases and avoid the introduction of bubbles. Optional: aliquot SHP1; SHP-1; HCP; HCPH; HPTP1C; PTP-1C; SHP-1L; SH-PTP1 1x stock solutions for storage. Storage and Stability Related Products The lyophilized powder is stable for at least 4 weeks at room temperature. It is recommended that the Product Name Catalog Number lyophilized and resuspended siRNAs are stored at or PTPN1 (PTP1B), Active P28-20G below -20oC. After resuspension, siRNA stock solutions ≥2 PTPN11 (SHP2), Active P38-21G µM can undergo up to 50 freeze-thaw cycles without PTPN12 (PTP-PEST), Active P39-21G significant degradation. For long-term storage, it is PTPN13 (FAP-1), Active P40-21G recommended that the siRNA is stored at -70oC. For most PTPN2 (TC-PTP), Active P29-20G favorable performance, avoid repeated handling and PTPN6 (SHP1), Active P33-20G multiple freeze/thaw cycles. PTPN7 (LC-PTP), Active P34-20G Anti-PTPN11 (SHP2) P38-63CR Scientific Background Anti-PTPN11 (SHP2) P38-63BR PTPN6 gene is preferentially expressed in a variety of hematopoietic cells, and is an early response gene in lymphokine stimulated cells (1). The noncatalytic N- terminus of this PTP can interact with MAP kinases and negatively regulates ERK2 and p38 MAP-kinases activity PTPN6 siRNA Set I (2). The PTPN6 was shown to be involved in the regulation siRNA duplexes targeted against three exon regions of T cell antigen receptor (TCR) signaling, which was thought to function through dephosphorylating the Catalog # P33-911 molecules related to MAP kinase pathway. Lot # Z2085-25 Packaging Specifications 2.5 nmol/tube for 3 x 5 nmol References Format Lyophilized powder 1. Adachi, M. et al: Protein-tyrosine phosphatase Stability 1yr at -70oC from date of shipment Storage & Shipping The lyophilized powder is stable for at expression in pre-B cell NALM-6. Cancer Res. 52: 737- least 4 weeks at room temperature. It is 740, 1992. recommended that the lyophilized 2. Pettiford, S M. et al: The MAP-kinase ERK2 is a specific and resuspended siRNAs are stored at o substrate of the protein tyrosine phosphatase HePTP. or below -20 C. After resuspension, siRNA stock solutions ≥2 µM can Oncogene. 2000 Feb 17;19(7):858-69. undergo up to 50 freeze-thaw cycles without significant degradation. For long-term storage, it is recommended that the siRNA is stored at -70oC. For most favorable performance, avoid repeated handling and multiple freeze/thaw cycles. To place your order, please contact us by phone 1-(604)-232-4600, fax 1-604-232-4601 or by email: [email protected] www.signalchem.com FOR IN VITRO RESEARCH PURPOSES ONLY. NOT INTENDED FOR USE IN HUMAN OR ANIMALS. .
Recommended publications
  • Identification of Chebulinic Acid As a Dual Targeting Inhibitor of Protein
    Bioorganic Chemistry 90 (2019) 103087 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Short communication Identification of chebulinic acid as a dual targeting inhibitor of protein T tyrosine phosphatases relevant to insulin resistance Sun-Young Yoona,1, Hyo Jin Kangb,1, Dohee Ahna, Ji Young Hwanga, Se Jeong Kwona, ⁎ Sang J. Chunga, a School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea b Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea ARTICLE INFO ABSTRACT Keywords: Natural products as antidiabetic agents have been shown to stimulate insulin signaling via the inhibition of the Protein tyrosine phosphatases (PTPs) protein tyrosine phosphatases relevant to insulin resistance. Previously, we have identified PTPN9 and DUSP9 as Chebulinic acid potential antidiabetic targets and a multi-targeting natural product thereof. In this study, knockdown of PTPN11 Type 2 diabetes increased AMPK phosphorylation in differentiated C2C12 muscle cells by 3.8 fold, indicating that PTPN11 could Glucose-uptake be an antidiabetic target. Screening of a library of 658 natural products against PTPN9, DUSP9, or PTPN11 PTPN9 identified chebulinic acid (CA) as a strong allosteric inhibitor with a slow cooperative binding toPTPN9 PTPN11 (IC50 = 34 nM) and PTPN11 (IC50 = 37 nM), suggesting that it would be a potential antidiabetic candidate. Furthermore, CA stimulated glucose uptake and resulted in increased AMP-activated protein kinase (AMPK) phosphorylation. Taken together, we demonstrated that CA increased glucose uptake as a dual inhibitor of PTPN9 and PTPN11 through activation of the AMPK signaling pathway. These results strongly suggest that CA could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.
    [Show full text]
  • PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers
    Published OnlineFirst March 28, 2016; DOI: 10.1158/0008-5472.CAN-15-1501 Cancer Priority Report Research PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers David P. Labbe1,2, Noriko Uetani1,Valerie Vinette1,3, Laurent Lessard4, Isabelle Aubry1, Eva Migon1, Jacinthe Sirois1, Jody J. Haigh5, Louis R. Begin 6, Lloyd C. Trotman7, Marilene Paquet8, and Michel L. Tremblay1,2,3 Abstract Diet affects the risk and progression of prostate cancer, but vation, interpreted to reflect a heightened sensitivity to IGF-1 the interplay between diet and genetic alterations in this disease stimulation upon HFD feeding. Prostate-specific overexpres- is not understood. Here we present genetic evidence in the sion of PTP1B was not sufficienttoinitiateprostatecancer, mouse showing that prostate cancer progression driven by arguingthatitactedasadiet-dependentmodifier of prostate À À loss of the tumor suppressor Pten is mainly unresponsive to cancer development in Pten / mice. Our findings offer a a high-fat diet (HFD), but that coordinate loss of the protein preclinical rationale to investigate the anticancer effects of tyrosine phosphatase Ptpn1 (encoding PTP1B) enables a highly PTP1B inhibitors currently being studied clinically for diabetes À À À À invasive disease. Prostate cancer in Pten / Ptpn1 / mice treatment as a new modality for management of prostate was characterized by increased cell proliferation and Akt acti- cancer. Cancer Res; 76(11); 3130–5. Ó2016 AACR. Introduction metabolism and cancer and is now a validated therapeutic target for diabetes, obesity, and breast cancer (7). Prostate cancer is the most frequently diagnosed cancer in The promise of PTP1B-directed therapeutics prompted us to North American men and is the second leading cause of can- further characterize the role of PTP1B in prostate cancer initiation cer-related deaths (1).
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Inflammatory Cytokine Signalling by Protein Tyrosine Phosphatases in Pancreatic Β-Cells
    59 4 W J STANLEY and others PTPN1 and PTPN6 modulate 59: 4 325–337 Research cytokine signalling in β-cells Differential regulation of pro- inflammatory cytokine signalling by protein tyrosine phosphatases in pancreatic β-cells William J Stanley1,2, Prerak M Trivedi1,2, Andrew P Sutherland1, Helen E Thomas1,2 and Esteban N Gurzov1,2,3 Correspondence should be addressed 1 St. Vincent’s Institute of Medical Research, Melbourne, Australia to E N Gurzov 2 Department of Medicine, St. Vincent’s Hospital, The University of Melbourne, Melbourne, Australia Email 3 ULB Center for Diabetes Research, Universite Libre de Bruxelles (ULB), Brussels, Belgium esteban.gurzov@unimelb. edu.au Abstract Type 1 diabetes (T1D) is characterized by the destruction of insulin-producing β-cells Key Words by immune cells in the pancreas. Pro-inflammatory including TNF-α, IFN-γ and IL-1β f pancreatic β-cells are released in the islet during the autoimmune assault and signal in β-cells through f protein tyrosine phosphorylation cascades, resulting in pro-apoptotic gene expression and eventually phosphatases β-cell death. Protein tyrosine phosphatases (PTPs) are a family of enzymes that regulate f PTPN1 phosphorylative signalling and are associated with the development of T1D. Here, we f PTPN6 observed expression of PTPN6 and PTPN1 in human islets and islets from non-obese f cytokines diabetic (NOD) mice. To clarify the role of these PTPs in β-cells/islets, we took advantage f inflammation Journal of Molecular Endocrinology of CRISPR/Cas9 technology and pharmacological approaches to inactivate both proteins. We identify PTPN6 as a negative regulator of TNF-α-induced β-cell death, through JNK- dependent BCL-2 protein degradation.
    [Show full text]
  • Supplementary Materials
    Supplementary Suppl. Figure 1: MAPK signalling pathway of A: NCI-H2502, B: NCI-H2452, C: MSTO-211H and D: MRC-5. Suppl. Figure 2: Cell cycle pathway of A: NCI-H2502, B: NCI-H2452, C: MSTO-211H and D: MRC- 5. Suppl. Figure 3: Cancer pathways of A: NCI-H2502, B: NCI-H2452, C: MSTO-211H and D: MRC-5. Suppl. Figure 4: Phosphorylation level of A: ARAF, B: EPHA1, C: EPHA2, D: EPHA7 in all cell lines. For each cell line, phosphorylation levels are depicted before (Medium) and after cisplatin treatment (Cis). Suppl. Figure 5: Phosphorylation Level of A: KIT, B: PTPN11, C: PIK3R1, D: PTPN6 in all cell lines. For each cell line, phosphorylation levels are depicted before (Medium) and after cisplatin treatment (Cis). Suppl. Figure 6: Phosphorylation Level of A: KDR, B: EFS, C: AKT1, D: PTK2B/FAK2 in all cell lines. For each cell line, phosphorylation levels are depicted before (Medium) and after cisplatin treatment (Cis). Suppl. Figure 7: Scoreplots and volcanoplots of PTK upstream kinase analysis: A: Scoreplot of PTK- Upstream kinase analysis for NCI-H2052 cells. B: Volcanoplot of PTK-Upstream kinase analysis for NCI-H2052 cells. C: Scoreplot of PTK-Upstream kinase analysis for NCI-H2452 cells. D: Volcanoplot of PTK-Upstream kinase analysis for NCI-H2452 cells. E: Scoreplot of PTK-Upstream kinase analysis for MSTO-211H cells. F: Volcanoplot of PTK-Upstream kinase analysis for MSTO- 211H cells. G: Scoreplot of PTK-Upstream kinase analysis for MRC-5cells. H: Volcanoplot of PTK- Upstream kinase analysis for MRC-5 cells. Suppl. Figure 8: Scoreplots and volcanoplots of STK upstream kinase analysis: A: Scoreplot of STK- Upstream kinase analysis for NCI-H2052 cells.
    [Show full text]
  • The Expression Patterns and the Prognostic Roles of PTPN Family Members in Digestive Tract Cancers
    Preprint: Please note that this article has not completed peer review. The expression patterns and the prognostic roles of PTPN family members in digestive tract cancers CURRENT STATUS: UNDER REVIEW Jing Chen The First Affiliated Hospital of China Medical University Xu Zhao Liaoning Vocational College of Medicine Yuan Yuan The First Affiliated Hospital of China Medical University Jing-jing Jing The First Affiliated Hospital of China Medical University [email protected] Author ORCiD: https://orcid.org/0000-0002-9807-8089 DOI: 10.21203/rs.3.rs-19689/v1 SUBJECT AREAS Cancer Biology KEYWORDS PTPN family members, digestive tract cancers, expression, prognosis, clinical features 1 Abstract Background Non-receptor protein tyrosine phosphatases (PTPNs) are a set of enzymes involved in the tyrosyl phosphorylation. The present study intended to clarify the associations between the expression patterns of PTPN family members and the prognosis of digestive tract cancers. Method Expression profiling of PTPN family genes in digestive tract cancers were analyzed through ONCOMINE and UALCAN. Gene ontology enrichment analysis was conducted using the DAVID database. The gene–gene interaction network was performed by GeneMANIA and the protein–protein interaction (PPI) network was built using STRING portal couple with Cytoscape. Data from The Cancer Genome Atlas (TCGA) were downloaded for validation and to explore the relationship of the PTPN expression with clinicopathological parameters and survival of digestive tract cancers. Results Most PTPN family members were associated with digestive tract cancers according to Oncomine, Ualcan and TCGA data. For esophageal carcinoma (ESCA), expression of PTPN1, PTPN4 and PTPN12 were upregulated; expression of PTPN20 was associated with poor prognosis.
    [Show full text]
  • The Regulatory Roles of Phosphatases in Cancer
    Oncogene (2014) 33, 939–953 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW The regulatory roles of phosphatases in cancer J Stebbing1, LC Lit1, H Zhang, RS Darrington, O Melaiu, B Rudraraju and G Giamas The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies. Oncogene (2014) 33, 939–953; doi:10.1038/onc.2013.80; published online 18 March 2013 Keywords: cancer; phosphatases; solid tumours GASTROINTESTINAL MALIGNANCIES abs in sera were significantly associated with poor survival in Oesophageal cancer advanced ESCC, suggesting that they may have a clinical utility in Loss of PTEN (phosphatase and tensin homologue deleted on ESCC screening and diagnosis.5 chromosome 10) expression in oesophageal cancer is frequent, Cao et al.6 investigated the role of protein tyrosine phosphatase, among other gene alterations characterizing this disease. Zhou non-receptor type 12 (PTPN12) in ESCC and showed that PTPN12 et al.1 found that overexpression of PTEN suppresses growth and protein expression is higher in normal para-cancerous tissues than induces apoptosis in oesophageal cancer cell lines, through in 20 ESCC tissues.
    [Show full text]
  • Genetic Alterations of Protein Tyrosine Phosphatases in Human Cancers
    Oncogene (2015) 34, 3885–3894 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Genetic alterations of protein tyrosine phosphatases in human cancers S Zhao1,2,3, D Sedwick3,4 and Z Wang2,3 Protein tyrosine phosphatases (PTPs) are enzymes that remove phosphate from tyrosine residues in proteins. Recent whole-exome sequencing of human cancer genomes reveals that many PTPs are frequently mutated in a variety of cancers. Among these mutated PTPs, PTP receptor T (PTPRT) appears to be the most frequently mutated PTP in human cancers. Beside PTPN11, which functions as an oncogene in leukemia, genetic and functional studies indicate that most of mutant PTPs are tumor suppressor genes. Identification of the substrates and corresponding kinases of the mutant PTPs may provide novel therapeutic targets for cancers harboring these mutant PTPs. Oncogene (2015) 34, 3885–3894; doi:10.1038/onc.2014.326; published online 29 September 2014 INTRODUCTION tyrosine/threonine-specific phosphatases. (4) Class IV PTPs include Protein tyrosine phosphorylation has a critical role in virtually all four Drosophila Eya homologs (Eya1, Eya2, Eya3 and Eya4), which human cellular processes that are involved in oncogenesis.1 can dephosphorylate both tyrosine and serine residues. Protein tyrosine phosphorylation is coordinately regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases 1 THE THREE-DIMENSIONAL STRUCTURE AND CATALYTIC (PTPs). Although PTKs add phosphate to tyrosine residues in MECHANISM OF PTPS proteins, PTPs remove it. Many PTKs are well-documented oncogenes.1 Recent cancer genomic studies provided compelling The three-dimensional structures of the catalytic domains of evidence that many PTPs function as tumor suppressor genes, classical PTPs (RPTPs and non-RPTPs) are extremely well because a majority of PTP mutations that have been identified in conserved.5 Even the catalytic domain structures of the dual- human cancers are loss-of-function mutations.
    [Show full text]
  • Supplementary Data
    Progressive Disease Signature Upregulated probes with progressive disease U133Plus2 ID Gene Symbol Gene Name 239673_at NR3C2 nuclear receptor subfamily 3, group C, member 2 228994_at CCDC24 coiled-coil domain containing 24 1562245_a_at ZNF578 zinc finger protein 578 234224_at PTPRG protein tyrosine phosphatase, receptor type, G 219173_at NA NA 218613_at PSD3 pleckstrin and Sec7 domain containing 3 236167_at TNS3 tensin 3 1562244_at ZNF578 zinc finger protein 578 221909_at RNFT2 ring finger protein, transmembrane 2 1552732_at ABRA actin-binding Rho activating protein 59375_at MYO15B myosin XVB pseudogene 203633_at CPT1A carnitine palmitoyltransferase 1A (liver) 1563120_at NA NA 1560098_at AKR1C2 aldo-keto reductase family 1, member C2 (dihydrodiol dehydrogenase 2; bile acid binding pro 238576_at NA NA 202283_at SERPINF1 serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), m 214248_s_at TRIM2 tripartite motif-containing 2 204766_s_at NUDT1 nudix (nucleoside diphosphate linked moiety X)-type motif 1 242308_at MCOLN3 mucolipin 3 1569154_a_at NA NA 228171_s_at PLEKHG4 pleckstrin homology domain containing, family G (with RhoGef domain) member 4 1552587_at CNBD1 cyclic nucleotide binding domain containing 1 220705_s_at ADAMTS7 ADAM metallopeptidase with thrombospondin type 1 motif, 7 232332_at RP13-347D8.3 KIAA1210 protein 1553618_at TRIM43 tripartite motif-containing 43 209369_at ANXA3 annexin A3 243143_at FAM24A family with sequence similarity 24, member A 234742_at SIRPG signal-regulatory protein gamma
    [Show full text]
  • High Expression of MAPK-14 Promoting the Death of Chondrocytes Is an Important Signal of Osteoarthritis Process
    High expression of MAPK-14 promoting the death of chondrocytes is an important signal of osteoarthritis process Zhiqin Deng1,*, Xiaotian Hu1,2,*, Murad Alahdal1, Jianquan Liu1, Zhe Zhao1, Xiaoqiang Chen1, Junxiong Xie1, Li Duan1, Daping Wang1,2 and Wencui Li1 1 Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong, China 2 Anhui Medical University, Hefei, China * These authors contributed equally to this work. ABSTRACT Background. Osteoarthritis (OA) is one of the most common degenerative diseases worldwide. Many researchers are studying the pathogenesis of OA, however, it is still unclear. Methods. Screening and validation of OA relevant hub genes are an important part of exploring their potential molecular mechanism. Therefore, this study aims to explore and verify the mechanisms of hub genes in the OA by bioinformatics, qPCR, fluorescence and propidium iodide staining. Results. Microarray datasets GSE43923, GSE55457 and GSE12021 were collected in the Gene Expression Omnibus (GEO), including 45 samples, which divided into 23 osteoarthritis knee joint samples and 22 samples of normal knee joint. Thereafter, 265 differentiallyexpressedgenes (DEGs) were identified in all, which divided into 199 upregulated genes and 66 downregulated genes. The hub genes MAPK-14, PTPRC, PTPN12 were upregulated, while B9D1 was downregulated. In order to further Submitted 19 June 2020 confirm the expression of screening differential genes in human chondrocytes, the Accepted 7 December 2020 human chondrocytes were extracted from a joint replacement surgery and stained Published 15 January 2021 with toluidine blue for identification. Compared with normal chondrocytes, OA Corresponding authors chondrocytes had high expression of COL I protein and low expression of COL II Daping Wang, protein.
    [Show full text]
  • Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia
    cancers Review Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia Kalpana K. Bhanumathy 1,*, Amrutha Balagopal 1, Frederick S. Vizeacoumar 2 , Franco J. Vizeacoumar 1,3, Andrew Freywald 2 and Vincenzo Giambra 4,* 1 Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (A.B.); [email protected] (F.J.V.) 2 Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (F.S.V.); [email protected] (A.F.) 3 Cancer Research Department, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada 4 Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy * Correspondence: [email protected] (K.K.B.); [email protected] (V.G.); Tel.: +1-(306)-716-7456 (K.K.B.); +39-0882-416574 (V.G.) Simple Summary: Protein phosphorylation is a key regulatory mechanism that controls a wide variety of cellular responses. This process is catalysed by the members of the protein kinase su- perfamily that are classified into two main families based on their ability to phosphorylate either tyrosine or serine and threonine residues in their substrates. Massive research efforts have been invested in dissecting the functions of tyrosine kinases, revealing their importance in the initiation and progression of human malignancies. Based on these investigations, numerous tyrosine kinase inhibitors have been included in clinical protocols and proved to be effective in targeted therapies for various haematological malignancies.
    [Show full text]
  • Activation of Islet Inflammation by Cytokine Signalling in Pancreatic Β
    Activation of Islet Inflammation by Cytokine Signalling in Pancreatic b-cells Understanding the Role of Protein Tyrosine Phosphatases William James Stanley ORCID: 0000-0001-8001-2359 Student Number: 515467 Submitted in Total Fulfilment of The Degree of Doctor of Philosophy March 2020 St. Vincent’s Institute of Medical Research Department of Medicine (St. Vincent’s Hospital) The University of Melbourne Abstract: Type 1 diabetes is characterised by the autoimmune destruction of insulin producing β- cells in the islets of Langerhans of the pancreas. Immune cells release pro-inflammatory cytokines such as interferon-g (IFN-g), tumour necrosis factor-a (TNF-a) and interleukin- 1b (IL-1b) into the islet microenvironment which activate phosphorylation cascades and gene expression in b-cells that increase their susceptibility to autoimmune attack and destruction. Protein tyrosine phosphatases (PTPs) regulate phosphorylation based signalling pathways and have previously been shown to negatively regulate IFN-g induced cell death of β-cells in vitro. We previously showed that during immune infiltration to the islet PTPs, including PTPN1 and PTPN6, are rendered catalytically inactive through oxidation resulting in loss of signal regulation. The overall aim of this thesis is to observe if antioxidant treatment can reduce autoimmune development in the NOD/Lt mouse through reduction of oxidised PTPs and dissect the role of PTPN1 and PTPN6 in the regulation of cytotoxic signalling events in the NIT-1 β-cell line and isolated NODPI islets in vitro. Chapter 3 studies the effect of the mitochondrial targeted antioxidant mito-TEMPO on insulitis and diabetes development in the NOD/Lt mouse. Delivery of mito-TEMPO through drinking water reduced levels of oxidised PTPs in the pancreas of NOD/Lt mice but had no effect on the development of insulitis, activity or number of CD8+ and CD4+ T- cells in the periphery in NOD/Lt mice or diabetes development in a diabetes transfer model.
    [Show full text]