MARCH5 Requires MTCH2 to Coordinate Proteasomal Turnover of the MCL1:NOXA Complex
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Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma
cancers Article Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma Nabanita Mukherjee 1, Carol M. Amato 2 , Jenette Skees 1, Kaleb J. Todd 1, Karoline A. Lambert 1, William A. Robinson 2, Robert Van Gulick 2, Ryan M. Weight 2, Chiara R. Dart 2, Richard P. Tobin 3, Martin D. McCarter 3, Mayumi Fujita 1,4,5 , David A. Norris 1,4 and Yiqun G. Shellman 1,5,* 1 Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Mail Stop 8127, Aurora, CO 80045, USA; [email protected] (N.M.); [email protected] (J.S.); [email protected] (K.J.T.); [email protected] (K.A.L.); [email protected] (M.F.); [email protected] (D.A.N.) 2 Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, Mail Stop 8117, Aurora, CO 80045, USA; [email protected] (C.M.A.); [email protected] (W.A.R.); [email protected] (R.V.G.); [email protected] (R.M.W.); [email protected] (C.R.D.) 3 Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; [email protected] (R.P.T.); [email protected] (M.D.M.) 4 Dermatology Section, Department of Veterans Affairs Medical Center, Denver, CO 80220, USA 5 Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA * Correspondence: [email protected]; Tel.: +1-303-724-4034; Fax: +1-303-724-4048 Received: 30 June 2020; Accepted: 31 July 2020; Published: 5 August 2020 Abstract: There is an urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations. -
Synergy of Bcl2 and Histone Deacetylase Inhibition Against Leukemic Cells from Cutaneous T-Cell Lymphoma Patients Benoit Cyrenne
Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine January 2018 Synergy Of Bcl2 And Histone Deacetylase Inhibition Against Leukemic Cells From Cutaneous T-Cell Lymphoma Patients Benoit Cyrenne Follow this and additional works at: https://elischolar.library.yale.edu/ymtdl Recommended Citation Cyrenne, Benoit, "Synergy Of Bcl2 And Histone Deacetylase Inhibition Against Leukemic Cells From Cutaneous T-Cell Lymphoma Patients" (2018). Yale Medicine Thesis Digital Library. 3388. https://elischolar.library.yale.edu/ymtdl/3388 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. i Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the Degree of Doctor of Medicine Benoit M. Cyrenne 2018 ii SYNERGY OF BCL2 AND HISTONE DEACETYLASE INHIBITION AGAINST LEUKEMIC CELLS FROM CUTANEOUS T-CELL LYMPHOMA PATIENTS. Benoit Cyrenne, Julia Lewis, Jason Weed, Kacie Carlson, Fatima Mirza, Francine Foss, and Michael Girardi. Department of Dermatology, Yale University, School of Medicine, New Haven, CT. The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted. -
BCL-2 Family Proteins: Changing Partners in the Dance Towards Death
Cell Death and Differentiation (2018) 25, 65–80 OPEN Official journal of the Cell Death Differentiation Association www.nature.com/cdd Review BCL-2 family proteins: changing partners in the dance towards death Justin Kale1, Elizabeth J Osterlund1,2 and David W Andrews*,1,2,3 The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis. The affinities and relative abundance of the BCL-2 family proteins dictate the predominate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP. We highlight the core mechanisms of BCL-2 family regulation of MOMP with an emphasis on how the interactions between the BCL-2 family proteins govern cell fate. We address the critical importance of both the concentration and affinities of BCL-2 family proteins and show how differences in either can greatly change the outcome. Further, we explain the importance of using full-length BCL-2 family proteins (versus truncated versions or peptides) to parse out the core mechanisms of MOMP regulation by the BCL-2 family. Finally, we discuss how post- translational modifications and differing intracellular localizations alter the mechanisms of apoptosis regulation by BCL-2 family proteins. Successful therapeutic intervention of MOMP regulation in human disease requires an understanding of the factors that mediate the major binding interactions between BCL-2 family proteins in cells. Cell Death and Differentiation (2018) 25, 65–80; doi:10.1038/cdd.2017.186; published online 17 November 2017 The membrane plays an active role in most BCL-2 family interactions by changing the affinities and local relative abundance of these proteins. -
The AAA-Atpase P97 Is Essential for Outer Mitochondrial Membrane Protein Turnover
MBoC | ARTICLE The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover Shan Xu a, b,* , Guihong Peng a, b,* , Yang Wang a, c , Shengyun Fang a, c , and Mariusz Karbowskia, b a Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, MD 21201; b Department of Biochemistry & Molecular Biology, c Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201 ABSTRACT Recent studies have revealed a role for the ubiquitin/proteasome system in the Monitoring Editor regulation and turnover of outer mitochondrial membrane (OMM)-associated proteins. Al- Benjamin Glick though several molecular components required for this process have been identifi ed, the University of Chicago mechanism of proteasome-dependent degradation of OMM-associated proteins is currently Received: Sep 3 , 2010 unclear. We show that an AAA-ATPase, p97, is required for the proteasomal degradation of Revised: Oct 26 , 2010 Mcl1 and Mfn1, two unrelated OMM proteins with short half-lives. A number of biochemical Accepted: Nov 18 , 2010 assays, as well as imaging of changes in localization of photoactivable GFP-fused Mcl1, re- vealed that p97 regulates the retrotranslocation of Mcl1 from mitochondria to the cytosol, prior to, or concurrent with, proteasomal degradation. Mcl1 retrotranslocation from the OMM depends on the activity of the ATPase domain of p97. Furthermore, p97-mediated retrotranslocation of Mcl1 can be recapitulated in vitro, confi rming a direct mitochondrial role for p97. Our results establish p97 as a novel and essential component of the OMM-associated protein degradation pathway. INTRODUCTION Mitochondria are the primary site of energy production in animal such as mitochondrial membrane dynamics. -
RING-Type E3 Ligases: Master Manipulators of E2 Ubiquitin-Conjugating Enzymes and Ubiquitination☆
Biochimica et Biophysica Acta 1843 (2014) 47–60 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr Review RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination☆ Meredith B. Metzger a,1, Jonathan N. Pruneda b,1, Rachel E. Klevit b,⁎, Allan M. Weissman a,⁎⁎ a Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, 1050 Boyles Street, Frederick, MD 21702, USA b Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195, USA article info abstract Article history: RING finger domain and RING finger-like ubiquitin ligases (E3s), such as U-box proteins, constitute the vast Received 5 March 2013 majority of known E3s. RING-type E3s function together with ubiquitin-conjugating enzymes (E2s) to medi- Received in revised form 23 May 2013 ate ubiquitination and are implicated in numerous cellular processes. In part because of their importance in Accepted 29 May 2013 human physiology and disease, these proteins and their cellular functions represent an intense area of study. Available online 6 June 2013 Here we review recent advances in RING-type E3 recognition of substrates, their cellular regulation, and their varied architecture. Additionally, recent structural insights into RING-type E3 function, with a focus on im- Keywords: RING finger portant interactions with E2s and ubiquitin, are reviewed. This article is part of a Special Issue entitled: U-box Ubiquitin–Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. Ubiquitin ligase (E3) Published by Elsevier B.V. Ubiquitin-conjugating enzyme (E2) Protein degradation Catalysis 1. -
Mechanisms Controlling Cell Life and Death Decisions
Department of Biological Regulation echanisms controlling cell Atan Gross Yehudit Zaltsman, Mlife and death decisions Natalie Yivgi-Ohana, Iris Kamer, Galia Oberkovitz, Liat Shachnai, Maria Maryanovich Programmed cell death or apoptosis in the extraembryonic (ExEm) region of is essential for both the development E7.5 wild type embryos, and this region and maintenance of tissue homeostasis is largely impaired in the Mtch2/Mimp-/- in multicellular organisms. The BCL-2 embryos. Thus, Mtch2/Mimp might play family members are critical regulators a critical role in the formation of the 972 8 934 3656 of the apoptotic program, whereas ExEm region. To study the connection the caspase proteases are the major between Mtch2/Mimp and apoptosis FAX 972 8 934 4116 executioners of this program. Members we generated Mtch2/Mimp-/- stable [email protected] of the BCL-2 family include both anti- and embryonic stem (ES) cell lines carrying www.weizmann.ac.il/ pro-apoptotic proteins. The BH3-only either an empty vector or Mtch2/Mimp. Biological_Regulation/gross proteins (e.g., BID) are an important Using these lines we demonstrated that subset of the pro-apoptotic proteins the presence of Mtch2/Mimp sensitizes that act as sentinels of intercellular cells to tBID-induced MOMP. Thus, we damage. In our laboratory, we are discovered that Mtch2/Mimp is critical S phase and inhibition of apoptosis focused on elucidating the mechanisms for normal embryonic development, following DNA damage. This surprising that balance between cell life and and is an important positive regulator and new pro-survival function of BID death, and BID is one of our primary of tBID-induced apoptosis at the is regulated by its phosphorylation tools to study these mechanisms. -
MARCH5-Dependent Degradation of MCL1/NOXA Complexes Defines
Cell Death & Differentiation (2020) 27:2297–2312 https://doi.org/10.1038/s41418-020-0503-6 ARTICLE MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment 1 1 1 2 2 1,3,4 Manuel D. Haschka ● Gerlinde Karbon ● Claudia Soratroi ● Katelyn L. O’Neill ● Xu Luo ● Andreas Villunger Received: 7 August 2019 / Revised: 17 January 2020 / Accepted: 21 January 2020 / Published online: 3 February 2020 © The Author(s) 2020. This article is published with open access Abstract Cells experiencing delays in mitotic progression are prone to undergo apoptosis unless they can exit mitosis before proapoptotic factors reach a critical threshold. Microtubule targeting agents (MTAs) arrest cells in mitosis and induce apoptotic cell death engaging the BCL2 network. Degradation of the antiapoptotic BCL2 family member MCL-1 is considered to set the time until onset of apoptosis upon MTA treatment. MCL1 degradation involves its interaction with one of its key binding partners, the proapoptotic BH3-only protein NOXA. Here, we report that the mitochondria-associated E3- ligase MARCH5, best known for its role in mitochondrial quality control and regulation of components of the mitochondrial fission machinery, controls the levels of MCL1/NOXA protein complexes in steady state as well as during mitotic arrest. 1234567890();,: 1234567890();,: Inhibition of MARCH5 function sensitizes cancer cells to the proapoptotic effects of MTAs by the accumulation of NOXA and primes cancer cells that may undergo slippage to escape death in mitosis to cell death in the next G1 phase. We propose that inhibition of MARCH5 may be a suitable strategy to sensitize cancer cells to antimitotic drug treatment. -
Multi-Modal Effects of 1B3, a Novel Synthetic Mir-193A-3P Mimic, Support Strong Potential for Therapeutic Intervention in Oncology
www.oncotarget.com Oncotarget, 2021, Vol. 12, (No. 5), pp: 422-439 Research Paper Multi-modal effects of 1B3, a novel synthetic miR-193a-3p mimic, support strong potential for therapeutic intervention in oncology Bryony J. Telford1, Sanaz Yahyanejad1, Thijs de Gunst1, Harm C. den Boer1, Rogier M. Vos1, Marieke Stegink1, Marion T.J. van den Bosch1, Mir Farshid Alemdehy1, Laurens A.H. van Pinxteren1, Roel Q.J. Schaapveld1 and Michel Janicot1 1InteRNA Technologies BV, Utrecht, The Netherlands Correspondence to: Michel Janicot, email: [email protected] Keywords: miR-193a-3p; microRNA mimic; microRNA delivery in vivo; pleiotropic mechanism of microRNA Received: October 16, 2020 Accepted: February 01, 2021 Published: March 02, 2021 Copyright: © 2021 Telford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Compelling evidence demonstrates that miR-193a-3p is a tumor suppressor microRNA in many cancer types, and its reduced expression is linked to cancer initiation and progression, metastasis, and therapy resistance. However, its mechanism of action is not consistently described between studies, and often contradicts the pleiotropic role of a microRNA in manipulating several different mRNA targets. We therefore comprehensively investigated miRNA-193a-3p's mode of action in a panel of human cancer cell lines, with a variety of genetic backgrounds, using 1B3, a synthetic microRNA mimic. Interestingly, the exact mechanism through which 1B3 reduced cell proliferation varied between cell lines. 1B3 efficiently reduced target gene expression, leading to reduced cell proliferation/survival, cell cycle arrest, induction of apoptosis, increased cell senescence, DNA damage, and inhibition of migration. -
Cops5 Safeguards Genomic Stability of Embryonic Stem Cells Through Regulating Cellular Metabolism and DNA Repair
Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair Peng Lia, Lulu Gaoa, Tongxi Cuia, Weiyu Zhanga, Zixin Zhaoa, and Lingyi Chena,1 aState Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Collaborative Innovation Center for Biotherapy, Tianjin Key Laboratory of Protein Sciences, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, 300071 Tianjin, China Edited by Janet Rossant, Hospital for Sick Children, University of Toronto, Toronto, Canada, and approved December 24, 2019 (received for review August 29, 2019) The highly conserved COP9 signalosome (CSN), composed of 8 transiently expressed in about 5% of ESCs at a given time, subunits (Cops1 to Cops8), has been implicated in pluripotency promotes rapid telomere elongation by telomere recombination maintenance of human embryonic stem cells (ESCs). Yet, the mech- and regulates genomic stability (11). Induced by genotoxic stress, anism for the CSN to regulate pluripotency remains elusive. We Filia stimulates the PARP1 activity and relocates from centro- previously showed that Cops2, independent of the CSN, is essential somes to DNA damage sites and mitochondria to regulate DDR for the pluripotency maintenance of mouse ESCs. In this study, we and apoptosis (12). Sall4, a pluripotency transcription factor, set out to investigate how Cops5 and Cops8 regulate ESC differ- facilitates the ataxia telangiectasia-mutated activation in re- entiation and tried to establish Cops5 and Cops8 knockout (KO) sponse to DSBs (13). To minimize the ROS-induced genomic ESC lines by CRISPR/Cas9. To our surprise, no Cops5 KO ESC clones DNA damage, ESCs produce lower levels of mitochondrial ROS were identified out of 127 clones, while three Cops8 KO ESC lines and express higher levels of antioxidants than differentiated cells were established out of 70 clones. -
Anti-NOXA Antibody (ARG64942)
Product datasheet [email protected] ARG64942 Package: 100 μg, 50 μg anti-NOXA antibody Store at: -20°C Summary Product Description Goat Polyclonal antibody recognizes NOXA Tested Reactivity Hu Tested Application WB Host Goat Clonality Polyclonal Isotype IgG Target Name NOXA Antigen Species Human Immunogen C-TQLRRFGDKLNFRQK Conjugation Un-conjugated Alternate Names NOXA; APR; Phorbol-12-myristate-13-acetate-induced protein 1; PMA-induced protein 1; Immediate- early-response protein APR; Protein Noxa Application Instructions Application table Application Dilution WB 0.03 - 0.1 µg/ml Application Note WB: Recommend incubate at RT for 1h. * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Calculated Mw 6 kDa Properties Form Liquid Purification Purified from goat serum by ammonium sulphate precipitation followed by antigen affinity chromatography using the immunizing peptide. Buffer Tris saline (pH 7.3), 0.02% Sodium azide and 0.5% BSA Preservative 0.02% Sodium azide Stabilizer 0.5% BSA Concentration 0.5 mg/ml Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C or below. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. www.arigobio.com 1/2 Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Database links GeneID: 5366 Human Swiss-port # Q13794 Human Gene Symbol PMAIP1 Gene Full Name phorbol-12-myristate-13-acetate-induced protein 1 Function Promotes activation of caspases and apoptosis. -
Knockout of Vdac1 Activates Hypoxia-Inducible Factor Through
Brahimi-Horn et al. Cancer & Metabolism (2015) 3:8 DOI 10.1186/s40170-015-0133-5 Cancer & Metabolism RESEARCH Open Access Knockout of Vdac1 activates hypoxia- inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation M. Christiane Brahimi-Horn1†, Sandy Giuliano1†, Estelle Saland2, Sandra Lacas-Gervais3, Tatiana Sheiko4, Joffrey Pelletier1, Isabelle Bourget5, Frédéric Bost6, Chloé Féral5, Etienne Boulter5, Michel Tauc7, Mircea Ivan8, Barbara Garmy-Susini9, Alexandra Popa10, Bernard Mari10, Jean-Emmanuel Sarry2, William J. Craigen4, Jacques Pouysségur1,11 and Nathalie M. Mazure1* Abstract Background: Mitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. Mitochondria are dynamic organelles that constantly undergo fusion and fission in response to environmental conditions. We showed previously that mitochondria of cells in a low oxygen environment (hypoxia) hyperfuse to form enlarged or highly interconnected networks with enhanced metabolic efficacy and resistance to apoptosis. Modifications to the appearance and metabolic capacity of mitochondria have been reported in cancer. However, the precise mechanisms regulating mitochondrial dynamics and metabolism in cancer are unknown. Since hypoxia plays a role in the generation of these abnormal mitochondria, we questioned if it modulates mitochondrial function. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) is at center stage in regulating metabolism and apoptosis. We demonstrated previously that VDAC1 was post-translationally C-terminal cleaved not only in various hypoxic cancer cells but also in tumor tissues of patients with lung adenocarcinomas. Cells with enlarged mitochondria and cleaved VDAC1 were also more resistant to chemotherapy-stimulated cell death than normoxic cancer cells. -
Downloaded As a Non-Linear Data Structure Containing Ordered Pairs of 68 Proteins and All the Other Proteins with Which They Interact
bioRxiv preprint doi: https://doi.org/10.1101/854695; this version posted November 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Network potential identifies therapeutic miRNA cocktails in Ewings Sarcoma Davis T. Weaver1, 2, *, Kathleen I. Pishas3,*, Drew Williamson4,*, Jessica Scarborough1, 2, Stephen L. Lessnick3, Andrew Dhawan2, 5, †, and Jacob G. Scott1, 2, 6, † 1Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA 2Translational Hematology Oncology Research, Cleveland Clinic, Cleveland OH, 44106, USA 3Nationwide Children’s Hospital, Columbus, Ohio, 43205 4Department of Pathology, Massachusetts General Hospital, Boston, MA, 02144 5Division of Neurology, Cleveland Clinic, Cleveland Ohio, 44195 6Department of Physics, Case Western Reserve University, Cleveland, OH, 44106, USA *contributed equally †[email protected], [email protected] ABSTRACT Introduction: Micro-RNA (miRNA)-based therapies are an emerging class of cancer therapies with many potential applications in the field owing to their ability to repress multiple, predictable targets and cause widespread changes in a cell signaling network. New miRNA-based oligonucleotide drugs have have shown significant promise for the treatment of cancer in pre-clinical studies. Because of the broad effects miRNAs can have on different cells and tissues, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets. Methods: In this work, we present a novel network science-based approach for identification of potential miRNA therapies, using Ewings Sarcoma as a model system.