In vivo Charakterisierung der Protein Kinase MK2 als potenzielles Zielmolekül für eine neue Chemotherapie-sensitivierende Krebstherapie

• Antragsteller: Professor Dr. Christian Reinhardt
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2009 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 154359109

• Erstellungsjahr: 2016

Zusammenfassung der Projektergebnisse

The project proposed for the Emmy-Noether group focused on the molecular details of the activation process of the cell cycle checkpoint kinase MK2. In addition, it was the declared goal of the Emmy-Noether group to identify clinical scenarios, in which pharmacological repression of MK2 might lead to anti-cancer activity. We have extensively investigated the molecular details of MK2 signaling and found that MK2 operates in a cytoplasmic feed forward loop to posttranscriptionally maintain active cell cycle checkpoints and to repress p53-driven apoptosis. In addition, we could demonstrate in vitro and in vivo that MK2 inhibition in combination with genotoxic chemotherapy displays selective toxicity against TP53-mutant tumors. We further showed that combined MK2/Chk1 inhibition displays selective cytotoxicity in KRAS- or BRAF-mutant carcinomas.

Projektbezogene Publikationen (Auswahl)

• DNA Damage activates A Spatially Distinct Late Cytoplasmic Cell Cycle Checkpoint Network Controlled by MK2-mediated RNA Stabilization. Mol Cell, 2010, 40;1, 34-49, 2010 Oct 8
  Reinhardt HC, Hasskamp P, Schmedding I, Morandell S, van Vugt M, Wang X, Linding R, Ong SE, Weaver D, Carr SA, Yaffe MB
  
• AATF/Che1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis. EMBO J, 2012 Oct 17;31(20):3961-75
  Höpker K, Hagmann H, Khurshid S, Chen S, Hasskamp P, Seeger-Nukpezah T, Schilberg K, Heukamp L, Lamkemeyer T, Sos M, Thomas R, Lowery D, Fischer M, Roels F, Liebau MC, Resch U, Kisner T, Röther F, Bartram MP, Müller RU, Fabretti F, Kurschat P, Schumacher B, Medema R, Yaffe MB, Schermer B, Reinhardt HC, Benzing T
  
• A novel Cre-versible approach identifies synthetic lethal interactions between MK2 and p53 in the DNA damage response in vivo. Cell Reports, 2013 Nov 27;5(4):868-77
  Morandell S, Reinhardt HC, Cannell IG, Kim JS, Ruf DM, Jacks T, Yaffe MB
  
• Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci Transl Med, 2013 Jun 12;5(189):189ra78
  Riabinska A, Daheim M, Herter-Sprie GS, Winkler J, Fritz C, Hallek M, Thomas RK, Kreuzer KA, Frenzel LP, Monfared P, Martins-Boucas JM, Chen S, Reinhardt HC
  
• A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. Cancer Discovery, 2014 May;4(5):592-605
  Dietlein F, Thelen L, Jokic M, Jachimowicz RD, Ivan L, Knittel G, Leeser U, van Oers J, Edelmann W, Heukamp LC, Reinhardt HC
  (Siehe online unter https://doi.org/10.1158/2159-8290.CD-13-0907)
• A synergistic interaction between Chk1- and MK2 inhibitors in KRAS-mutant cancer. Cell, 2015 Jul 2;162(1):146-59
  Dietlein F, Kalb B, Jokic M, Noll EM, Strong A, Tharun A, Ozretić L, Künstlinger H, Kambartel K, Randerath WJ, Jüngst C, Schmitt A, Torgovnick A, Richters A, Rauh D, Siedek F, Persigehl T, Mauch C, Bartkova J, Bradley A, Sprick MR, Trumpp A, Rad R, Saur D, Bartek J, Wolf J, Büttner R, Thomas RK, Reinhardt HC
  (Siehe online unter https://doi.org/10.1016/j.cell.2015.05.053)
• Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53. Cell Death Dis. 2015 May 21;6:e1764
  Desantis A, Bruno T, Catena V, De Nicola F, Goeman F, Iezzi S, Sorino C, Gentileschi MP, Germoni S, Monteleone V, Pellegrino M, Kann M, De Meo PD, Pallocca M, Höpker K, Moretti F, Mattei E, Reinhardt HC, Floridi A, Passananti C, Benzing T, Blandino G, Fanciulli M
  (Siehe online unter https://doi.org/10.1038/cddis.2015.117)
• Label-Free Protein-RNA Interactome Analysis Identifies Khsrp Signaling Downstream of the p38/Mk2 Kinase Complex as a Critical Modulator of Cell Cycle Progression. PLoS One. 2015 May 20;10(5):e0125745
  Boucas J, Fritz C, Schmitt A, Riabinska A, Thelen L, Peifer M, Leeser U, Nuernberg P, Altmueller J, Gaestel M, Dieterich C, Reinhardt HC
  (Siehe online unter https://doi.org/10.1371/journal.pone.0125745)