DOCSLIB.ORG

GSK-3Β Can Regulate the Sensitivity of MIA-Paca-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
GSK-3Β Can Regulate the Sensitivity of MIA-Paca-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals cells Article GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals Stephen L. Abrams 1, Shaw M. Akula 1, Akshaya K. Meher 1 , Linda S. Steelman 1, Agnieszka Gizak 2 , Przemysław Duda 2 , Dariusz Rakus 2 , Alberto M. Martelli 3 , Stefano Ratti 3 , Lucio Cocco 3 , Giuseppe Montalto 4,5, Melchiorre Cervello 5 , Peter Ruvolo 6, Massimo Libra 7,8 , Luca Falzone 7,8 , Saverio Candido 7,8 and James A. McCubrey 1,* 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Brody Building 5N98C, Greenville, NC 27858, USA; [email protected] (S.L.A.); [email protected] (S.M.A.); [email protected] (A.K.M.); [email protected] (L.S.S.) 2 Department of Molecular Physiology and Neurobiology, University of Wrocław, 50-335 Wrocław, Poland; [email protected] (A.G.); [email protected] (P.D.); [email protected] (D.R.) 3 Department of Biomedical and Neuromotor Sciences, Università di Bologna, 40126 Bologna, Italy; [email protected] (A.M.M.); [email protected] (S.R.); [email protected] (L.C.) 4 Department of Health Promotion, Maternal and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy; [email protected] 5 Institute for Biomedical Research and Innovation, National Research Council (CNR), 90133 Palermo, Italy; [email protected] 6 Citation: Abrams, S.L.; Akula, S.M.; Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; Meher, A.K.; Steelman, L.S.; Gizak, A.; [email protected] 7 Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Duda, P.; Rakus, D.; Martelli, A.M.; 95123 Catania, Italy; [email protected] (M.L.); [email protected] (L.F.); [email protected] (S.C.) Ratti, S.; Cocco, L.; et al. GSK-3β Can 8 Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy Regulate the Sensitivity of * Correspondence: [email protected]; Tel.: +1-(252)-744-2704; Fax: +1-(252)-744-3104 MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Abstract: Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently Chemotherapeutic Drugs, Targeted mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be Therapeutics and Nutraceuticals. Cells 2021, 10, 816. https://doi.org/ suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate 10.3390/cells10040816 the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells Academic Editor: Stephen Yarwood with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An Received: 7 March 2021 exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL Accepted: 4 April 2021 ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal Published: 6 April 2021 glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects Publisher’s Note: MDPI stays neutral of GSK-3 on MCF-7 breast cancer cells, which have mutant PIK3CA, were examined. KD-GSK-3β with regard to jurisdictional claims in increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction published maps and institutional affil- inhibitors. Thus, altering the levels of GSK-3β can have dramatic effects on sensitivity to drugs and iations. signal transduction inhibitors which may be influenced by the background of the tumor. Keywords: GSK-3β; targeted therapy; PDAC; breast cancer; KRas; β-catenin; BCL2; chemotherapeu- tic drugs; nutraceuticals Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Attribution (CC BY) license (https:// Glycogen synthase kinase-3 (GSK-3) is a family of kinases consisting of GSK-3α creativecommons.org/licenses/by/ and GSK-3β. The GSK-3 family members are highly conserved and expressed in many 4.0/). different types of cells and tissues [1–4]. They function as kinases and phosphorylate many Cells 2021, 10, 816. https://doi.org/10.3390/cells10040816 https://www.mdpi.com/journal/cells Cells 2021, 10, x 2 of 27 Cells 2021, 10, 816 1. Introduction 2 of 27 Glycogen synthase kinase-3 (GSK-3) is a family of kinases consisting of GSK-3α and GSK-3β. The GSK-3 family members are highly conserved and expressed in many differ- ent types of cells and tissues [1–4]. They function as kinases and phosphorylate many pro- proteins on serine (S) and threonine (T) residues [5–9]. After phosphorylation, their target teins on serine (S) and threonine (T) residues [5–9]. After phosphorylation, their target proteinsproteins are are often often inactivated. inactivated. GSK-3 GSK-3 kinases kinases play playkey roles key in roles many in biological many biological processes processes includingincluding aging, aging, diabetes, diabetes, inflammation, inflammation, meta metabolism,bolism, neural neural transmission, transmission, obesity, obesity,and and drug-resistancedrug-resistance [3,4,10–12]. [3,4,10–12 The]. The abilities abilities of GSK-3 of GSK-3β to influenceβ to influence the drug-sensitivity the drug-sensitivity of of pancreaticpancreatic cancer cancer cells cells and and breast breast cancer cancer cells cells are the are subjects the subjects of this of manuscript. this manuscript. GSK-3ββ isis often often considered considered to function to in concertfunction with in the concert PI3K/PTEN/AKT/mTORC1 with the andPI3K/PTEN/AKT/mTORC1 Wnt/β-catenin pathways and Wnt/ [10–16β-catenin]. An overview pathways of [10–16]. the interactions An overview with of the various in- signal- ingteractions pathways with andvarious sites signaling of certain pathways small molecule and sites of inhibitors certain small action molecule is presented inhibitors in Figure 1 . Oneaction of is thepresented best characterized in Figure 1. One reactions of the best involving characterized GSK-3 reactionsβ is its involving phosphorylation GSK-3β at S9 byis its AKT, phosphorylation which results at S9 in by its AKT, inactivation which results [6]. in GSK-3 its inactivationβ is then [6]. targeted GSK-3 forβ is proteasomalthen degradation.targeted for proteasomal Other kinases degradation. and phosphatases Other kinases and also phosphatases regulate GSK-3 also regulateβ activity GSK- by either 3β activity by either phosphorylation (e.g., protein kinase A (PKA), p70 ribosomal S6 ki- phosphorylation (e.g., protein kinase A (PKA), p70 ribosomal S6 kinase (p70S6K), and p90 nase (p70S6K), and p90 ribosomal S6 kinase (p90Rsk) [5,17–20] or dephosphorylation (e.g., ribosomal S6 kinase (p90Rsk)[5,17–20] or dephosphorylation (e.g., protein phosphorylase 1 protein phosphorylase 1 (PP1) and protein phosphatase 2A (PP2A)) at various regulatory (PP1)sites [21]. and protein phosphatase 2A (PP2A)) at various regulatory sites [21]. FigureFigure 1. 1. IllustrationIllustration of ofglycogen glycogen synthase synthase kinase-3 kinase-3 (GSK-3) (GSK-3) interactions interactions with other with signaling other signalingpath- path- waysways important in in regulation regulation of cell of cellgrowth growth and si andtes of sites interaction of interaction for certain for signal certain transduction signal transduction inhibitors used in this study. inhibitors used in this study. The PI3K/PTEN/AKT/mTORC1 pathway is often deregulated in human cancers due to mutations at PI3K (PIK3CA), PTEN, AKT, MTOR and tuberous sclerosis complex 2 (TSC2). Mutations that alter the activity of this pathway can be either activating (PIK3CA, AKT, and MTOR) or inactivating (PTEN and TSC2). Both types of mutations can lead to pathway activation [16,22]. In various cancers, including breast, prostate, and brain cancers, the PTEN tumor suppressor gene is frequently inactivated, which results in constitutive AKT activity that in turn inhibits GSK-3 activity. In pancreatic cancer, the upstream KRAS gene Cells 2021, 10, 816 3 of 27 is frequently mutated, which results in the activation of the PI3K/PTEN/AKT/mTORC1 pathway [23,24]. These events can lead to the activation of AKT, which in turn, leads to inactivation of GSK-3β. Thus, one of the converging points in cancer development is phosphorylation of GSK-3 and its subsequent inactivation. Silencing of GSK-3 can lead to activation of downstream molecules such as mTOR, which promote cell growth. Therefore, in many cancers with aberrant AKT activity, subsequent suppression of GSK-3 may prevent its normal negative regulatory effects on cellular proliferation. This may contribute to altered sensitivity to chemotherapeutic drugs, signal transduction inhibitors and nutraceuticals and the cancer cells can proliferate in an uncontrolled fashion. An example of this dysregulation is the effects of GSK-3 on the mechanistic target of rapamycin (mTORC1) activity. mTORC1 activity is important in cell growth and autophagy. mTORC1 activity is blocked by the immunosuppressive drug rapamycin and PI3K/mTOR dual inhibitors [14,15]. Both types of drugs are used to treat patients with various diseases. AMP-activated protein kinase (AMPK) can phosphorylate TSC2 at S1345, GSK-3β can then phosphorylate the TSC2 protein at T1329, S1333, S1337, and S1345. TSC2 activity is suppressed and results in inhibition of downstream Ras homolog enriched in brain (RHEB) which can normally activate mTORC1. In this scenario, mTORC1 is suppressed by GSK-3 and its ability to aid in the translation of growth-regulatory mRNAs which have unique 30ends, which are normally difficult to translate, is suppressed [10,14,15].
Load more

Recommended publications
  • Phosphoproteomic Characterization of Glycogen Synthase Kinase-3
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Phosphoproteomic Characterization Of Glycogen Synthase Kinase-3 Mansi Shinde University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Cell Biology Commons, Developmental Biology Commons, and the Pharmacology Commons Recommended Citation Shinde, Mansi, "Phosphoproteomic Characterization Of Glycogen Synthase Kinase-3" (2016). Publicly Accessible Penn Dissertations. 2583. https://repository.upenn.edu/edissertations/2583 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2583 For more information, please contact [email protected]. Phosphoproteomic Characterization Of Glycogen Synthase Kinase-3 Abstract Glycogen Synthase Kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed kinase that acts as a critical regulator of many signaling pathways. These pathways, when dysregulated, have been implicated in many human diseases, including bipolar disorder (BD), cancer, and diabetes. Over 100 putative GSK-3 substrates have been reported, based on direct kinase assays or genetic and pharmacological manipulation of GSK-3, in diverse cell types. Many more have been predicted based upon on the prevalence of the GSK-3 consensus sequence. As a result, there remains an unclear picture of the complete GSK-3 phosphoproteome. We have therefore used a large-scale mass spectrometry approach to analyze global changes in phosphorylation and describe the repertoire of GSK-3 substrates in a single cell type. For our studies, we used stable isotope labeling of amino acids in culture (SILAC) to compare the phosphoproteome of wild-type mouse embryonic stem cells (ESCs) to ESCs completely lacking Gsk3a and Gsk3b expression (Gsk3 DKO).
    [Show full text]
  • Gsk3β Mediates Muscle Pathology in Myotonic Dystrophy
    GSK3β mediates muscle pathology in myotonic dystrophy Karlie Jones, … , Nikolai A. Timchenko, Lubov T. Timchenko J Clin Invest. 2012;122(12):4461-4472. https://doi.org/10.1172/JCI64081. Research Article Muscle biology Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, and myotonia. DM1 is caused by the accumulation of CUG repeats, which alter the biological activities of RNA-binding proteins, including CUG-binding protein 1 (CUGBP1). CUGBP1 is an important skeletal muscle translational regulator that is activated by cyclin D3–dependent kinase 4 (CDK4). Here we show that mutant CUG repeats suppress Cdk4 signaling by increasing the stability and activity of glycogen synthase kinase 3β (GSK3β). Using a mouse model of DM1 (HSALR), we found that CUG repeats in the 3′ untranslated region (UTR) of human skeletal actin increase active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3β in both DM1 cell culture and mouse models corrected cyclin D3 levels and reduced muscle weakness and myotonia in DM1 mice. Our data predict that compounds normalizing GSK3β activity might be beneficial for improvement of muscle function in patients with DM1. Find the latest version: https://jci.me/64081/pdf Research article GSK3β mediates muscle pathology in myotonic dystrophy Karlie Jones,1 Christina Wei,1 Polina Iakova,2 Enrico Bugiardini,3 Christiane Schneider-Gold,4 Giovanni Meola,3 James Woodgett,5 James Killian,6 Nikolai A. Timchenko,2 and Lubov T. Timchenko1 1Department of Molecular Physiology and Biophysics and 2Department of Pathology and Immunology and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
    [Show full text]
  • Review of the Faculty of Medicine
    Review of the Faculty of Medicine University of Toronto 2010 Dr. Alastair Buchan, Professor of Stroke Medicine and Head of the Medical Sciences Division, University of Oxford; Dr. Richard Levin, Vice President Health Affairs and Dean of the Faculty of Medicine, McGill; Dr. Joseph B. Martin, Professor of Neurobiology and Dean Emeritus of the Harvard Medical School Introduction This review is written at the request of the Provost and follows the study of extensive materials provided by the Faculty and three days of meetings on site in Toronto (see Appendix A). The reviewers are very grateful to Meg Connell for all of her assistance in arranging an extensive schedule which included meetings with many members of the community representing the University, Departmental, Research Institute, Hospital Research Institutes and Hospital CEOs, and the Deanery Team. We are also very grateful to the Provost and her team, particularly Margie Halling. After agreement with the Provost, this report summarizes our major observations and does not respond specifically to the questions posed in the terms of reference. Executive Summary The reviewers were very impressed with the accomplishments of the University of Toronto, and in particular, the Faculty of Medicine and its Dean. The intention of the University of Toronto in going forward to its Bicentennial in 2030, is to be “a leader amongst the world’s best teaching and research universities in its discovery, preservation, and sharing of knowledge through its teaching and research and its commitment to excellence and equality”. Without a doubt the Faculty of Medicine, founded in 1843 and therefore 167 years old this year, is one of the preeminent Faculties of Medicine and as a total entity, one of North America’s and indeed the world’s largest and most prestigious Academic Health Science Centres.
    [Show full text]
  • Table of Contents
    Cyclical Review Fall 2012 Self-Study Department of Obstetrics & Gynaecology, University of Toronto Cyclical Review Self-Study Table of Contents 1. Executive Summary 1 2. Introduction and Context 3 2.1 Department Introduction 3 2.1.1. Appendix: Strategic Plan 2.2 Report of the Chair 9 3. People 11 3.1 Faculty Demographics 11 3.1.1 Primary Appointments 3.1.2 Cross Appointments 3.2 Residents 2012-2013 13 3.3 Fellows 2012-2013 14 3.3.1 Fellows by Alphabetical Order 14 3.3.2 Fellows by Program 15 4. Education 17 4.1 Undergraduate Education 17 4.1.1 Appendix: Details of Rotation at Each of the Teaching Sites 4.1.2 Appendix: Obstetrics and Gynaecology Clerkship – OBS310Y 4.1.3 Appendix: TRES Manual Logging Sheet 4.1.4 Appendix: Standardized Seminar Program 4.1.5 Appendix: Midrotation Feedback Form 4.1.6 Appendix: Clerkship Encounter Form 4.1.7 Appendix: OBS310Y Observed History and Physical Assessment Form 4.1.8 Appendix: Course Evaluation Data 4.2 Postgraduate Education – Residency Program 31 4.2.4.1 Appendix: Residency Program Committee (RPC) Terms of Reference 4.2.5.1 Appendix: Academic Half-Day Teaching 2012-13 4.3 Postgraduate Education – Fellowship Program 37 4.3.1 Description 37 4.3.2 Gynaecologic Oncology 41 4.3.3 Maternal-Fetal Medicine 43 4.3.4 Gynaecologic Reproductive Endocrinology and Infertility 45 4.4 Continuing Medical Education 47 4.4.1 CME Courses 4.4.2 Interhospital Rounds 4.5 Professional Development 49 4.5.1 Appendix: Faculty Development Workshops 4.5.2 Appendix: Leadership Council Presentations 5.
    [Show full text]
  • Calendar 2008-2009
    University of Toronto School of Graduate Studies 2008 / 2009 Calendar Graduate Programs: Web Site: Student Services at SGS: For admission and application www.sgs.utoronto.ca Telephone: (416) 978-6614 information, contact the graduate unit Fax: (416) 978-4367 directly. Contact information and Web E-mail: site addresses are listed in each unit's [email protected] entry. [email protected] 63/65 St. George Street, Toronto, Ontario, Canada, M5S 2Z9 Mission Statement Dean’s Welcome The mission of the School of Graduate Studies I am delighted to welcome you to the many graduate is to promote excellence in graduate education and communities of the University of Toronto. We are proud of research University-wide and ensure consistency and our accomplishments as a centre for graduate education high standards across the divisions. Sharing respon- that integrates advanced scholarship and research into sibility for graduate studies with graduate units and every degree program. Please use this site to learn more divisions, and operating through a system of collegial about the excellent programs we offer. governance, consultation and decanal leadership, Here at the largest graduate school in Canada, over SGS defines and administers university-wide regula- 13,000 graduate students are studying in an extraordi- tions for graduate education. nary range of scholarly fields. The diversity of our depart- SGS also provides expertise, advice and information; ments, centres, and institutes means that the focus and oversees the design and delivery of programs; organizes expertise that you seek is very likely to be found within reviews and develops performance standards; supports the graduate offerings at U of T.
    [Show full text]
  • Phosphoinositide-3-OH Kinase-Dependent Regulation of Glycogen Synthase Kinase 3 and Protein Kinase B͞AKT by the Integrin-Linked Kinase
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 11211–11216, September 1998 Cell Biology Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase ByAKT by the integrin-linked kinase MARC DELCOMMENNE*, CLARA TAN*†,VIRGINIA GRAY*, LAURENT RUE*‡,JAMES WOODGETT‡, AND SHOUKAT DEDHAR*†§ *British Columbia Cancer Agency, Jack Bell Research Centre, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6 Canada; †Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3 Canada; and ‡Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 810 University Avenue, Toronto, Ontario M5G 2M9 Canada Communicated by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, July 23, 1998 (received for review July 6, 1998) ABSTRACT Integrin-linked kinase (ILK) is an ankyrin- is negatively regulated in a Pi(3)K-dependent manner upon repeat containing serine–threonine protein kinase capable of insulin stimulation (8) and is also a critical component of the interacting with the cytoplasmic domains of integrin b1, b2, Wnt-signaling pathway (9). GSK-3 can phosphorylate highly and b3 subunits. Overexpression of ILK in epithelial cells conserved serine residues in the protein b-catenin in the disrupts cell–extracellular matrix as well as cell–cell inter- presence of adematous polyposis coli and axin (9). GSK-3 also actions, suppresses suspension-induced apoptosis (also called can regulate protein translation by phosphorylating and inac- Anoikis), and stimulates anchorage-independent cell cycle tivating eIF2B, the guanine nucleotide exchange factor for the progression. In addition, ILK induces nuclear translocation of translation initiation factor eIF2 (3).
    [Show full text]
  • Effect of Glycogen Synthase Kinase-3 Inactivation on Mouse Mammary Gland Development and Oncogenesis
    bioRxiv preprint doi: https://doi.org/10.1101/001321; this version posted July 26, 2014. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Role of GSK-3 in mammary gland tumorigenesis (Revised) Dembowy et al. Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis Joanna Dembowy1,2, Hibret A. Adissu3,4, Jeff C. Liu5, Eldad Zacksenhaus2, 4, 5 and James R. 1,2 Woodgett 1. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada 2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 3. Pathology Core, Centre for Modelling Human Disease, Toronto Centre for Phenogenomics, Toronto, Ontario, Canada 4. Toronto General Hospital Research Institute, Toronto, Ontario, Canada 5. Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada Address correspondence to: James Woodgett, Mount Sinai Hospital, Room 982, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5, Tel: 416-586-8811, [email protected] We declare no conflict of interest. Running title: Role of GSK-3 in mammary gland tumorigenesis bioRxiv preprint doi: https://doi.org/10.1101/001321; this version posted July 26, 2014. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Many components of Wnt/β-catenin signaling pathway have critical functions in mammary gland development and tumor formation, yet the contribution of glycogen synthase kinase-3 (GSK-3α and GSK-3β) to mammopoiesis and oncogenesis is unclear.
    [Show full text]
  • 2009-2010 Annual Report
    WORKING TOGETHER TO ADVANCE GENOMICS IN CANADA Abdallah Daar Peter Singer Aled Edwards Program Andrew Emili Andrew Macpherson Ontario Genomics Platform Affiliates Abdallah Daar Peter Singer Anthony Pawson Arturas Petronis Basil Arif Brenda Andrews Aled Edwards Andrew Emili Program Genomics Teaching Prize Summer Brent Zanke Cheryl Arrowsmith Chris Hogue Christian Burks Andrew Macpherson Anthony Pawson Research Fellowship Program Student Network Club Arturas Petronis Basil Arif Brenda Genome Pre-commercialization Business Development Fund Cynthia Guidos Daniel Figeys David MacLennan Gary Bader Geee! In Genome Tak Mak Canadian Barcode of Life Network Andrews Brent Zanke Cheryl Arrowsmith Quaid Morris Gilles Lajoie Jack Greenblatt James Woodgett Chris Hogue Christian Burks Cynthia Ontario Genomics Institute Annual Report 2010 Janet Rossant Jayne Danska Jeff Wrana John Coleman John Dick Guidos Daniel Figeys David MacLennan Celebrating 10 years of genomics leadership Gary Bader Quaid Morris Gilles Lajoie Katherine Siminovitch Kevin Kain Lap-Chee Tsui Lori Frappier Mark Jack Greenblatt James Woodgett Janet University of Guelph Genome Project The Hospital for Sick Children, Toronto Henkelman Mehrdad Hajibabaei Michael Rudnicki Paul Hebert Paul Rossant Jayne Danska Jeff Wrana John The Centre for Applied Genomics (TCAG) The Dynactome: Mapping Piunno Peter Durie Peter Liu Robert Hegele Scott Tanner Shana Kelley Coleman John Dick Katherine Siminovitch Spatio-Temporal Dynamic Systems in Humans Samuel Kevin Kain Lap-Chee Tsui Lori Frappier Lunenfeld
    [Show full text]
  • Stabilization of Я-Catenin by a Wnt-Independent Mechanism
    Stabilization of ␤-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth Syed Haq*†, Ashour Michael*, Michele Andreucci‡, Kausik Bhattacharya*, Paolo Dotto‡, Brian Walters*, James Woodgett§, Heiko Kilter*, and Thomas Force*† *Molecular Cardiology Research Institute, Tufts–New England Medical Center, and Tufts University School of Medicine, Boston, MA 02111; ‡Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and §University of Toronto, Toronto, Ontario, Canada M5S 1A1 Communicated by Alexander Leaf, Harvard University, Charlestown, MA, February 21, 2003 (received for review September 30, 2002) ␤-Catenin is a transcriptional activator that regulates embryonic phorylation inhibits GSK-3 activity directed toward primed development as part of the Wnt pathway and also plays a role in substrates that have been previously phosphorylated at a site tumorigenesis. The mechanisms leading to Wnt-induced stabiliza- four residues carboxy terminal to the GSK-3 phosphorylation tion of ␤-catenin, which results in its translocation to the nucleus site but does not inhibit kinase activity directed toward unprimed and activation of transcription, have been an area of intense substrates (15, 16). This mechanism is used in growth factor interest. However, it is not clear whether stimuli other than Wnts signaling but is not believed to be important in Wnt signaling and can lead to important stabilization of ␤-catenin and, if so, what has been reported to be insufficient to induce ␤-catenin accu- factors mediate that stabilization and what biologic processes mulation (17, 18). Although these data are compatible with might be regulated. Herein we report that ␤-catenin is stabilized in ␤-catenin being unprimed in situ (19), recent studies indicate that cardiomyocytes after these cells have been exposed to hypertro- ␤-catenin can exist as a primed target for GSK-3, when phos- phic stimuli in culture or in vivo.
    [Show full text]
  • Research Training Centre Samuel Lunenfeld Research Institute Mount Sinai Hospital
    Research Training Centre Samuel Lunenfeld Research Institute Mount Sinai Hospital 600 University Avenue Toronto, Ontario M5G 1X5 RESEARCH TRAINING CENTRE WWW.MSHRI.ON.CA/RTC www.mshri.on.ca/rtc For more information contact: Dr. Cindy Todoroff, Associate Director Tel: 416 586-4694 Email: [email protected] “ Pushing the limits of what will be possible in the future is what some of the world’s This is a tremendously exciting time to very best researchers are embark on a career in health research. doing today…right here at Trainees are the lifeblood of the Samuel Mount Sinai Hospital, in our Lunenfeld Research Institute of Mount Sinai Hospital. They are the bright minds and big mbe very own Samuel Lunenfeld hearts who lead the way in research and in Research Institute.” turn, advance the future health of Canadians. The Research Training Centre (RTC) within the Dr. James Woodgett, Director of Research Lunenfeld provides an exceptional research and learning environment for all trainees. And learning happens everywhere at the Lunenfeld. The RTC is not just a place, but a concept. It’s an administrative framework, an opportunity to get to know fellow scientists and a support system. We are highly committed to training young investigators. We support a collaborative environment and work together to help realize ideas—and dreams. We invite you to join us in the process of discovery. Dr. Stephen Lye Director, Research Training Centre Samuel Lunenfeld Research Institute Design: Duo Strategy & Design Inc. (duo.ca) / Photography: Michelle Gibson (michellegibsonphoto.com) Copywriting: Nikki Lusco The Samuel Lunenfeld Research Institute of Mount Sinai Hospital, a University of Toronto affiliated research centre, has established itself as one of the world’s leading biomedical research institutes.
    [Show full text]
  • Annual Report 2006-2007
    MOUNT SINAI HOSPITAL MOUNT SINAI HOSPITAL FOUNDATION SAMUEL LUNENFELD RESEARCH INSTITUTE OF MOUNT SINAI HOSPITAL 2006-07 REPORT ANNUAL HOSPITAL SINAI MOUNT OF INSTITUTE RESEARCH LUNENFELD SAMUEL FOUNDATION HOSPITAL SINAI MOUNT HOSPITAL SINAI MOUNT Mount Sinai HoSpital Mount Sinai HoSpital foundation SaMuel lunenfeld reSearcH inStitute of Mount Sinai H o S pital ANNuAl RepoRt 2006-2007 Bright Minds. Big Hearts. The Best Medicine. our Mission: Mount Sinai HoSpital iS dedicated to diScovering and delivering tHe beSt patient care witH tHe Heart and valueS true to our Heritage. Mount Sinai HoSpital Mount Sinai HoSpital foundation Mount Sinai Hospital is an internationally The Mount Sinai Hospital Foundation raises and recognized, 472-bed acute care academic health stewards funds to support Mount Sinai Hospital centre affiliated with the University of Toronto. and its Samuel Lunenfeld Research Institute. It is known for excellence in the provision The generous support of donors fuels Hospital of compassionate patient care, innovative initiatives and innovation, funds research, education and world-leading research. Our Centres improves facilities and technology, and new of Excellence are Women’s and Infants’ Health; programs at Mount Sinai. Surgical Sub-specialties and Oncology; Acute and Chronic Medicine; and Laboratory Medicine and Infection Control. SaMuel lunenfeld reSearcH inStitute of Mount Sinai Hospital brings together Bright Minds Mount Sinai HoSpital and Big Hearts to provide the Best Medicine. The Samuel Lunenfeld Research Institute is a recognized leader in the world’s research community, with a reputation for top-quality investigators and scientific excellence. It has an extensive impact on scientific advancement and is home to many of Canada’s outstanding biomedical researchers.
    [Show full text]
  • Charles W. Tran , Samuel D. Saibil , Pamela S. Ohashi
    Cellular pathways modulating the activity of the E3 ubiquitin ligase Cbl-b in regulating T cell function Charles W. Tran, Samuel D. Saibil, Pamela S. Ohashi The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada Department of Immunology, University of Toronto, Toronto, Ontario, Canada p14+ GSK3(αβ)fl/fl Background Results Lck Cre- Lck Cre+ 0 24 48 0 24 48 MW (kDa) Figure 5. Reduced levels of Cbl-b in p14 TCR Casitas B lymphoma b (Cbl-b) is a master regulator of immune function in T cells, Western blot analysis revealed reduced Cbl-b levels in both PKB transgenic T cells transgenic T cells lacking GSK-3 at various 109 and represents a promising target for the immunotherapy of many diseases (Fig. 2A) and T cells treated with GSK-3 inhibitors or T cells lacking GSK-3 (Fig. 2B, 4A, Cbl-b timepoints post-stimulation. including cancer, type 1 diabetes, and chronic viral infection. 4B). Two conserved GSK-3 consensus sites were also identied in Cbl-b (Fig 3A), and Cbl-b was rst identied as an important regulator of T cell immunity . Cbl-b only the phosphorylation of one site was altered in the presence of GSK-3 inhibitor XII (Fig. 3B) or in PKB transgenic T cells (Fig. 3C). functions as an E3 ubiquitin ligase, and has been shown to have many target substrates including PLC-γ1, TCR-ζ, and Vav-1. Cbl-b is important for the 20 maintenance of peripheral tolerance and the loss of Cbl-b results in the development A B of systemic autoimmunity.
    [Show full text]