Prof. Dr. Thorsten Stiewe
Genomic stress: demise and resurrection of the guardian angel p53
Hazards from the environment or originating within our body constantly challenge the integrity of our DNA and cause genomic stress. As genomic stability is essential for health at the cellular, organismal or species level, our cells have developed coping mechanisms to deal with DNA damage. This is centrally coordinated by the p53 protein, which is therefore dubbed ‘guardian of the genome’. When p53 fails, this ultimately triggers cancer. It is therefore not surprising that p53 mutations are the most frequent alterations observed in cancer cells and that drugs which restore the anti-cancer activity of mutant p53 are considered a holy grail of tumor therapy. However, fixing a broken protein is pharmacologically far from trivial and no p53 mutant is like the other. I will present experimental insight from our lab into the complexity of the p53 mutome, discuss functional consequences and clinical implications of distinct p53 mutations, and highlight novel concepts for therapeutic p53 restoration.
Date of Birth: 15.11.1970
2006 Habilitation, Biochemistry and Molecular Biology, University of Würzburg
2000 Dr. med., University of Essen
1997 State examination in Medicine, University of Essen
Employment and Positions
2015 – present Director of the Institute of Molecular Oncology
2010 – present Head of Genomics Core Facility, Philipps University Marburg
2010 – present Professor of Molecular Oncology (W3), Philipps University Marburg
2007 – 2010 Professor of Molecular Oncology (W2), Philipps University Marburg
2002 – 2007 Junior Group Leader, Rudolf-Virchow-Center (DFG Research Center for Experimental Biomedicine), University of Würzburg
2000 – 2002 Post-doctoral fellow, Institute of Molecular Biology, West German Cancer Center, University of Essen
1997 – 2000 Graduate student, Institute of Molecular Biology, West German Cancer Center, University of Essen
2012 – present Member of the Steering Committee of the Universities of Gießen and Marburg Lung Center (UGMLC), Coordinator of the section "Lung Cancer"
2011 – present Member of the German Center for Lung Research (DZL)
2008 – 2013 Coordinator of the DFG Integrated Graduate School "Molecular Cancer Biology" (SFB/Transregio TR17)
2004 – 2013 Executive board member of the DFG Transregio TR17 "Ras-dependent pathways in human cancer"
Awards and Honours
2014 Award for Research on Animal Welfare of the Federal State of Hesse
2010 European Research Council Starting Grant
2007 C.G. Schmidt Medal for Cancer Research
2002 Junior Group Award by the DFG Research Center Würzburg
2002 Wissenschaftspreis Medizin, University Essen
2001 Forschungspreis Westdeutsches Tumorzentrum e.V.
Ten most important publications
Timofeev O, Klimovich B, Schneikert J, Wanzel M, Pavlakis E, Noll J, Mutlu S, Elmshäuser S, Nist A, Mernberger M, Lamp B, Wenig U, Brobeil A, Gattenlöhner S, Köhler K, Stiewe T (2019). Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses. EMBO J, in press.
Stiewe T, Haran TE (2018). How mutations shape p53 interactions with the genome to promote tumorigenesis and drug resistance. 38, 27-43. (review article)
Vogiatzi F, Brandt DT, Schneikert J, Fuchs J, Grikscheit K, Wanzel M, Pavlakis E, Charles JP, Timofeev O, Nist A, Mernberger M, Kantelhardt EJ, Siebolts U, Bartel F, Jacob R, Rath A, Moll R, Grosse R, (2016). Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5. 113, E8433-E8442.
Wanzel M, Vischedyk JB, Gittler MP, Gremke N, Seiz JR, Hefter M, Noack M, Savai R, Mernberger M, Charles JP, Schneikert J, Bretz AC, Nist A, Stiewe T (2016). CRISPR-Cas9-based target validation for p53-reactivating model compounds. 12, 22–28.
Charles JP, Fuchs J, Hefter M, Vischedyk JB, Kleint M, Vogiatzi F, Schäfer JA, Nist A, Timofeev O, Wanzel M, Stiewe T (2014). Monitoring the dynamics of clonal tumour evolution in vivo using secreted luciferases. Nat Commun 5, e3981.
Timofeev O, Schlereth K, Wanzel M, Braun A, Nieswandt B, Pagenstecher A, Rosenwald A, Elsässer HPStiewe T (2013). p53 DNA binding cooperativity is essential for apoptosis and tumor suppression in vivo. 3, 585-97.
Schlereth K, Beinoraviciute-Kellner R, Zeitlinger MK, Bretz AC, Sauer M, Charles JP, Vogiatzi F, Leich E, Samans B, Eilers M, Kisker C, Rosenwald A, Stiewe T (2010). DNA binding cooperativity of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell 38, 356-68.
Stiewe T (2007). The p53 family in differentiation and tumorigenesis. 7, 165-8. (review article)
Cam H, Griesmann H, Beitzinger M, Hofmann L, Beinoraviciute-Kellner R, Sauer M, Huttinger-Kirchhof N, Oswald C, Friedl P, Gattenlohner S, Burek C, Rosenwald A, Stiewe T (2006). p53 family members in myogenic differentiation and rhabdomyosarcoma development. 10, 281-93.
Stiewe T, Pützer BM (2000). Role of the p53-homologue p73 in E2F1-induced apoptosis. 26, 464-9.