vincristine; C. elegans; chemotherapy; germ line; Phagocytosis; apoptosis; programmed cell death; genotoxic stress; model organism; cancer
Pinto Sérgio M., Almendinger Johann, Cabello Juan, Hengartner Michael O. (2016), Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans, in PLOS ONE
, 11(2), e0149274-e0149274.
Pinto Sérgio M, Almendinger Johann, Cabello Juan, Hengartner Michael O (2016), Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans., in PloS one
, 11(2), 0149274-0149274.
Kamkina Polina, Snoek L. Basten, Grossmann Jonas, Volkers Rita J. M., Sterken Mark G., Daube Michael, Roschitzki Bernd, Fortes Claudia, Schlapbach Ralph, Roth Alexander, von Mering Christian, Hengartner Michael O., Schrimpf Sabine P., Kammenga Jan E. (2016), Natural Genetic Variation Differentially Affects the Proteome and Transcriptome in Caenorhabditis elegans, in Molecular & Cellular Proteomics
, 15(5), 1670-1680.
Singh Kapil Dev, Roschitzki Bernd, Snoek L. Basten, Grossmann Jonas, Zheng Xue, Elvin Mark, Kamkina Polina, Schrimpf Sabine P., Poulin Gino B., Kammenga Jan E., Hengartner Michael O. (2016), Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways, in PLOS ONE
, 11(3), e0149418-e0149418.
Subasic Deni, Stoeger Thomas, Eisenring Seline, Matia-González Ana M, Imig Jochen, Zheng Xue, Xiong Lei, Gisler Pascal, Eberhard Ralf, Holtackers René, Gerber André P, Pelkmans Lucas, Hengartner Michael O (2016), Post-transcriptional control of executioner caspases by RNA-binding proteins., in Genes & development
, 30(19), 2213-2225.
Galluzzi L, Bravo-San Pedro J M, Vitale I, Aaronson S A, Abrams J M, Adam D, Alnemri E S, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, Baehrecke E H, Bazan N G, Bertrand M J, Bianchi K, Blagosklonny M V, Blomgren K, Borner C, Bredesen D E, Brenner C, Campanella M, Candi E, Cecconi F, Chan F K, Chandel N S, Cheng E H (2015), Essential versus accessory aspects of cell death: recommendations of the NCCD 2015., in Cell death and differentiation
, 22(1), 58-73.
Sievert Henning, Pällmann Nora, Miller Katharine K, Hermans-Borgmeyer Irm, Venz Simone, Sendoel Ataman, Preukschas Michael, Schweizer Michaela, Boettcher Steffen, Janiesch P Christoph, Streichert Thomas, Walther Reinhard, Hengartner Michael O, Manz Markus G, Brümmendorf Tim H, Bokemeyer Carsten, Braig Melanie, Hauber Joachim, Duncan Kent E, Balabanov Stefan (2014), A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation., in Disease models & mechanisms
, 7(8), 963-76.
Sendoel Ataman, Hengartner Michael O (2014), Apoptotic cell death under hypoxia., in Physiology (Bethesda, Md.)
, 29(3), 168-76.
Sendoel Ataman, Maida Simona, Zheng Xue, Teo Youjin, Stergiou Lilli, Rossi Carlo-Alberto, Subasic Deni, Pinto Sergio M, Kinchen Jason M, Shi Moyin, Boettcher Steffen, Meyer Joel N, Manz Markus G, Bano Daniele, Hengartner Michael O (2014), DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis., in Nature cell biology
, 16(8), 812-20.
Neukomm L J, Zeng S, Frei A P, Huegli P A, Hengartner M O (2014), Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans, in Cell Death and Differentiation
, 21(6), 845-853.
Meyer Joel N, Leung Maxwell C K, Rooney John P, Sendoel Ataman, Hengartner Michael O, Kisby Glen E, Bess Amanda S (2013), Mitochondria as a target of environmental toxicants., in Toxicological sciences : an official journal of the Society of Toxicology
, 134(1), 1-17.
Tholey Andreas, Treitz Christian, Kussmann Martin, Bendixen Emöke, Schrimpf Sabine P, Hengartner Michael O (2013), Model organisms proteomics--from holobionts to human nutrition., in Proteomics
, 13(17), 2537-41.
Eberhard Ralf, Stergiou Lilli, Hofmann E Randal, Hofmann Jen, Haenni Simon, Teo Youjin, Furger André, Hengartner Michael O (2013), Ribosome synthesis and MAPK activity modulate ionizing radiation-induced germ cell apoptosis in Caenorhabditis elegans., in PLoS genetics
, 9(11), 1003943-1003943.
Snoek L Basten, Van der Velde K Joeri, Arends Danny, Li Yang, Beyer Antje, Elvin Mark, Fisher Jasmin, Hajnal Alex, Hengartner Michael O, Poulin Gino B, Rodriguez Miriam, Schmid Tobias, Schrimpf Sabine, Xue Feng, Jansen Ritsert C, Kammenga Jan E, Swertz Morris A (2013), WormQTL--public archive and analysis web portal for natural variation data in Caenorhabditis spp., in Nucleic acids research
, 41(Database i), 738-43.
Pinto Sérgio Morgado, Hengartner Michael Otmar (2012), Cleaning up the mess: cell corpse clearance in Caenorhabditis elegans., in Current opinion in cell biology
, 24(6), 881-8.
Vermezovic J, Stergiou L, Hengartner M O, d'Adda di Fagagna F (2012), Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans., in Cell death and differentiation
, 19(11), 1847-55.
Apoptosis is an important component of animal development and homeostasis. Defects in the regulation of the apoptotic program have been implicated in the aetiology of cancer, autoimmune diseases, myocardial heart infarct, stroke, and neurodegenerative diseases. The small nematode Caenorhabditis elegans has been used with great success as a model organism for the genetic analysis of programmed cell death. Extensive studies in this organism have shown that the molecular machinery responsible for apoptotic death is conserved between nematodes and humans. Thus, information gained about nematode cell death is likely to shed light on the regulation of apoptosis in mammals. In this grant application, we propose to use C. elegans as a genetic model system to study two interesting and important questions related to apoptosis. In Project A, we will dissect the signaling pathway that mediates germ cell apoptosis in response to vincristine treatment. Antitubulin chemotherapeutics such as vincristine can suppress microtubule dynamics, resulting in mitotic arrest and apoptosis. How defects in microtubule dynamics induce apoptosis is however still largely unclear. We recently found that the C. elegans gene LET-99 and its human homologue are specifically required for vincristine-induced apoptosis. To better understand this process, we will:• Identify and characterize the kinase signaling pathway that mediates vincristine- and LET-99-dependent apoptosis.• Identify and characterize of LET-99-interacting proteins in the C. elegans germ line.• Identify and characterize additional modulators of vincristine-induced germ cell apoptosis.In Project B, we investigate continue our analysis of how apoptotic cells are recognized and cleared from the body. As is the case for the apoptotic program, the molecular program that mediates clearance of apoptotic cells has been suggested to play important roles in the maintenance of homeostasis. We recently set up a sensitive new GFP-based genetic screen for mutations that modulate either the survival or clearance of six specific neurons (Pn.aap cells) in C. elegans. Using this assay, we isolated over 18 strains with reduced Pn.aap cells and 8 strains with increased Pn.aap cells. In the current funding period, we will: • Determine the biological process affected by mutations that alter Pn.aap cell numbers.• Identify the genes affected by these new “Pn.aap mutations”.• Characterize at the genetic and molecular levels the most interesting new genes isolated in this screen.The work that we propose to do in this grant proposal should significantly improve our understanding of the signaling pathway that mediates apoptosis following vincristine treatment, and might identify new genes that, when altered, can contribute to the development to resistance to antitubulin treatment. We also expect to gain new insights into the signaling pathways that mediate apoptotic cell recognition, uptake, and degradation. Because apoptotic pathways are largely conserved through evolution, we expect that our findings will indirectly also improve our understanding of these processes in humans.