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Seiteninhalt
Scientific Focus
Our research mainly focuses on the molecular mechanisms of apoptosis, non-apoptotic cell death and autophagy. In one part of our studies, we are elucidating the molecular events leading to gliomagenesis, as well as apoptosis deficiency and therapy resistance of glioblastoma multiforme, the most malignant and deadly human primary brain tumor. Based on these investigations, we are trying to develop novel genetic insight-based therapeutic strategies for the treatment of gliomas in cell culture models and in transplantable syngeneic animal tumor models. Another major aim in our lab is to identify the relevant pathophysiological stress stimuli and cell death signalling pathways implicated in apoptotic neuron death in stroke, Alzheimer´s disease and Parkinson´s disease. In this context, we are especially interested in the transcriptional stress responses and mitochondrial events underlying cell death and cell survival decisions in neurons.
Research Interests
Mechanisms of programmed cell death, acute and chronic cns damage, neuronal stress signalling, physiological and pathophysiological roles of the amyloid precursor protein and its family members, mitochondrial control of cell death, target-specific therapies for the treatment of brain tumors, oncogenic signalling pathways, autophagy in health and disease, mechanisms of tumor cell migration and invasion.
Major Current Projects
Mechanisms of autophagic cell death in apoptosis-deficient cancer cells
http://www.fan.uni-frankfurt.de/wiki/index.php/Donat_Koegel
STAT3 as a therapeutic target for the treatment of glioma
Investigating the role of APP family members in stress signalling and aging
http://www.uni-heidelberg.de/app-function/projects/tp7.html
Funding
German Research Foundation (DFG) German Cancer Aid (Deutsche Krebshilfe) LOEWE program, state of Hessia (OSF) Federal Ministry of Education and Research (BMBF)
Methods
Assays for detection of apoptosis (Caspase assays, FACS Annexin/propidium iodide, measurement of mitochondrial membrane potentials), autophagy (LC3 conversion and translocation, autophagic flux of GFP-LC3-RFP, p62 degradation, FACS Lysotracker) and cell viability (MTT assay), cultivation of primary neurons, in vitro hypoxia/ischemia models, reporter gene assays, siRNA techniques, lentiviral gene transfer, live cell imaging, in vivo brain tumor models, in vitro models for cell migration and invasion.
Group members
Cooperation Partners
External
Prof. Dr. Christian Behl, Institute for Pathobiochemistry, Johannes Gutenberg University Mainz Prof. Dr. Jochen Prehn, RCSI, Dublin, Ireland Prof. Dr. Andreas von Deimling, Dept. of Neuropathology, Ruprecht-Karls-University Heidelberg Prof. Dr. Till Acker, Dept. of Neuropathology, Justus-Liebig University Giessen Prof. Dr. Stefan Kins, Dept. of Biology, University of Kaiserslautern Dr. Thorsten Müller, Functional Proteomics, Ruhr University Bochum PD Dr. Michael Bette, Institute of Anatomy and Cell Biology, Philipps-University Marburg
Frankfurt
Prof. Dr. Bernd Groner, Georg Speyer Haus, Frankfurt Dr. Christian Behrends, Inst. of Biochemistry II, Goethe University Frankfurt Prof. Dr. Thomas Deller, Dept. of Clin. Neuroanatomy, Goethe University Frankfurt PD Dr. Martin Zörnig, Georg Speyer Haus, Frankfurt Prof. Dr. Michel Mittelbronn, Edinger Institute, Goethe University Frankfurt Prof. Dr. Walter E. Müller, PD Dr. Gunter Eckert, Dept. of Pharmacology, Goethe University Frankfurt Prof. Dr. Joachim Steinbach, Dept. of Neurooncology, Goethe University Frankfurt Prof. Dr. Abdelhaq Rami, Dept. of Neuroanatomy, Goethe University Frankfurt Dr. Francesco Pampaloni, FMLS, Frankfurt
Publications
Original papers
1. Kögel D, Aboud M, Flügel RM. (1995) Molecularbiological characterization of the human foamy virus reverse transcriptase and ribonuclease H domain. Virology 213, 97-108.
2. Kögel D, Aboud M, Flügel RM. (1995) Mutational analysis of the reverse transcriptase and ribonuclease H domain of the human foamy virus. Nucleic Acids Research 23, 2621-2625.
3. Kögel D, Plöttner O, Landsberg G, Christian S, Scheidtmann KH. (1998) Cloning and characterization of Dlk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones. Oncogene 17: 2645-2654.
4. Kögel D, Bierbaum H, Preuss U, Scheidtmann KH. (1999) C-terminal truncation of Dlk/ZIP kinase leads to abrogation of nuclear transport and high apoptotic activity. Oncogene 18: 7212-7218.
5. Page G, Kögel D, Rangnekar V, Scheidtmann KH. (1999) Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis. Oncogene 18: 7265-7273.
6. Page G, Lödige I, Kögel D, Scheidtmann KH. (1999) AATF, a novel transcription factor that interacts with Dlk/ZIP kinase and interferes with apoptosis. FEBS Lett. 462: 187-191.
7. Poppe M, Reimertz C, Düßmann H, Krohn AJ, Luetjens CM, Bockelmann D, Nieminen AL, Kögel D, Prehn JH. (2001) Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis.
8. Reimertz C*, Kögel D*, Lankiewicz S, Poppe M, Prehn JH. (2001) Ca2+-Induced Inhibition of Neuronal Apoptosis: Degradation of Apoptotic Protease Activating Factor-1 (APAF-1). J Neurochem. 78: 1256-1266.
9. Luetjens CM*, Kögel D*, Reimertz C, Düßmann H, Renz A, Schulze-Osthoff K, Nieminen A-L, Poppe M, Prehn JH. (2001) Multiple kinetics of mitochondrial cytochrome c release in drug-induced apoptosis. Mol. Pharm. 60: 1008-1019.
10. Kögel D, Reimertz C, Mech P, Poppe M, Frühwald M, Engemann H, Scheidtmann KH, Prehn JH. (2001) Dlk/ZIP kinase-induced apoptosis in Human Medulloblastoma Cells: Requirement of the Mitochondrial Apoptosis Pathway. Brit. J Cancer, 85: 1801-1808.
11. Wobser H, Düßmann H, Kögel D, Wang H, Reimertz C, Wollheim CB, Byrne MM, Prehn JH. (2002) Dominant-Negative Suppression of HNF-1alpha Results in Mitochondrial Dysfunction, beta-cell apoptosis, and Increased Sensitivity to Ceramide-, But Not High Glucose-Induced Cell Death. J. Biol. Chem. 277:6413-6421.
12. Poppe M, Reimertz C, Münstermann G, Kögel D, Prehn JH. (2002) Ceramide-Induced Cell Death of D283 Medulloblastoma Cells Requires Mitochondrial Respiratory Chain Activity. J. Neurochem. 82:482-494.
13. Engemann H, Kögel D, Manderscheid S, Preuss U, Scheidtmann KH. (2002) Elucidation of transcriptional elements and the genomic structure of DAP-like kinase. Ann N Y Acad Sci. 973: 363-367.
14. Rehm M, Düßmann H, Jänicke R, Tavare JM, Kögel D, Prehn JH. (2002) Single-cell fluorescence resonance energy transfer analysis demonstrates that caspase activation during apoptosis is a rapid process. Role of caspase-3. J Biol Chem. 277: 24506-24514.
15. Svensson B, Peters M, König HG, Poppe M, Levkau B, Rothermund M, Arolt V, Kögel D, Prehn JH. (2002) VEGF protects cultured rat hippocampal neurons against hypoxic injury. J Cereb Blood Flow Metab. 22: 1170-1175.
16. Kögel D, Reimertz C, Düßmann H, Mech P, Scheidtmann KH, Prehn JH. (2003) The Death Associated Protein (DAP) kinase homologue Dlk/ZIP kinase induces p19ARF- and p53-independent apoptosis. Eur J Cancer. 39: 249-256.
17. Düßmann H, Rehm M, Kögel D, Prehn, JH. (2003) Outer mitochondrial membrane permeabilization during apoptosis triggers caspase-independent mitochondrial and caspase-dependent plasma membrane potential depolarization: a single-cell analysis. J Cell Sci. 116: 525-536.
18. Düßmann H, Kögel D, Rehm M, Prehn, JH. (2003) Mitochondrial Membrane Permeabilization and Superoxide Production during Apoptosis. A SINGLE-CELL ANALYSIS. J Biol Chem. 278:12645-12649.
19. Kögel D, Schomburg R, Schürmann T, Reimertz C, Poppe M, Eckert A, Müller WE, Prehn JH (2003). The Amyloid Precursor Protein protects PC12 cells against ER stress-induced apoptosis. J Neurochem. 87: 248-256.
20. Reimertz C, Kögel D, Rami A, Chittenden T, Prehn JH (2003). Gene Expression during ER Stress-Induced Apoptosis in Neurons: Induction of the BH3-Only Protein Bbc3/PUMA and Activation of the Mitochondrial Apoptosis Pathway. J. Cell Biol. 162: 587-597.
21. Kögel D, Peters M, König H-G, Hashemi SMA, Bui NT, Arolt V, Rothermundt M, Prehn JHM (2004). S100B potently activates p65/c-Rel transcriptional complexes in hippocampal neurons: Clinical implications for the role of S100B in excitotoxic brain injury. Neuroscience 127: 913-920
22. Kögel D, Schomburg R, Copanaki K, Prehn JHM. (2005). Regulation of Gene Expression by the Amyloid Precursor Protein: Inhibition of the JNK/c-Jun Pathway. Cell Death Differ. 12, 1-9 (2005).
23. König H-G, Kögel D, Rami A, Prehn, JHM. (2005). TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling. J Cell Biol. 168: 1077-1086.
24. Chandra T, Maier W, König H-G, Hirzel K, Kögel D, Schüler T, Chandra A, Demirhan I, Laube B (2005). Molecular interactions of the HIV-1 Tat protein with NMDA receptor subunits. Neuroscience 134, 145-153.
25. Gerlach R, Demel G, König H-G, Groß U, Prehn JHM, Raabe A, Seifert V, Kögel D (2006). Active secretion of S100B from astrocytes during metabolic stress. Neuroscience, 141: 1697-1701.
26. Schultz C, König H-G, Del Turco D, Politi C, Eckert GP, Ghebremedhin E, Prehn JHM, Kögel D, Deller T (2006). Coincident enrichment of phosphorylated IκBα, activated IKK, and phosphorylated p65 in the axon initial segment of neurons. Mol Cell Neurosci, 33: 68-80.
27. Kögel D, Svensson B, Copanaki E, Anguissola S, Bonner C, Thurow N, Gudorf D, Hetschko H, Müller T, Peters M, König H-G, Prehn JHM (2006). Induction of Transcription Factor CHOP Mediates Hypoglycemia-Induced Necrotic Cell Death in Human Neuroblastoma Cells. J Neurochem, 99: 952-964.
28. Concannon CG, Koehler BF, Reimertz C, Murphy BM, Bonner C, Thurow N, Ward MW, Villunger A, Strasser A, Kögel D*, Prehn JHM* (2007). Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway. Oncogene, 26: 1681-1692.
29. Müller T, Concannon CG, Ward MW, Kögel D, Prehn JHM, Egensperger R (2007). Modulation of gene expression and cytoskeletal dynamics by the APP intracellular domain (AICD). Mol Biol Cell, 18: 201-210.
30. Copanaki E, Schürmann T, Eckert A, Leuner K, Müller WE, Prehn JHM*, Kögel D* (2007). The Amyloid Precursor Protein potentiates CHOP induction and cell death in response to ER Ca2+ depletion. BBA Mol Cell Res, 1773: 157-165.
31. Hetschko H, Voss V, Horn S, Seifert V, Prehn JHM, Kögel D. Pharmacological Inhibition of Bcl-2 Family Members Reactivates TRAIL-induced Apoptosis in Malignant Glioma. J Neuro-Oncol. 86: 265-272.
32. Hetschko H, Voss V, Senft C, Seifert V, Prehn JH, Kögel D (2008). BH3 mimetics reactivate autophagic cell death in anoxia-resistant malignant glioma cells. Neoplasia. 10: 873-885.
33. Köhler B, Anguissola S, Concannon CG, Rehm M, Kögel D, Prehn JH (2008). Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands' apoptotic and synergistic effects. PLoS ONE. 3: e2844.
34. Anguissola S, Köhler B, O'Byrne R, Düssmann H, Cannon MD, Murray FE, Concannon CG, Rehm M, Kögel D, Prehn JH (2009). Bid and calpains cooperate to trigger oxaliplatin-induced apoptosis of cervical carcinoma HeLa cells. Mol Pharmacol. 76: 998-1010.
35. Peters I, Igbavboa U, Schütt T, Haidari S, Hartig U, Rosello X, Böttner S, Copanaki E, Deller T, Kögel D, Wood WG, Müller WE, Eckert GP (2009). The interaction of beta-amyloid protein with cellular membranes stimulates its own production. BBA Biomembranes. 1788: 964-972.
36. Copanaki E, Chang S, Vlachos A, Tschäpe JA, Müller UC, Kögel D*, Deller T* (2010). sAPPalpha antagonizes dendritic degeneration and neuron death triggered by proteasomal stress. Mol Cell Neurosci. 44: 386-393.
37. Klinkenberg M, Thurow N, Gispert S, Ricciardi F, Eich F, Prehn JH, Auburger G, Kögel D (2010). Enhanced vulnerability of PARK6 patient skin fibroblasts to apoptosis induced by proteasomal stress. Neuroscience. 166: 422-434.
38. Gessler F, Voss V, Dützmann S, Seifert V, Gerlach R, Kögel D (2010). Inhibition of tissue factor/protease-activated receptor-2 signaling limits proliferation, migration and invasion of malignant glioma cells. Neuroscience. 165:1312- 1322.
39. Senft C, Polacin M, Priester M, Seifert V, Kögel D, Weissenberger J (2010). The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas. BMC Cancer10:491.
40. Senft C, Priester M, Polacin M, Seifert V, Kögel D, Weissenberger J (2011). Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells. J Neuro-Oncol. 101: 393-403.
41. Voss V, Senft C, Lang V, Ronellenfitsch MR, Steinbach JP, Seifert V, Kögel D (2010). The Pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Mol Cancer Res, 8: 1002-1016.
42. Weissenberger J, Priester M, Bernreuther C, Rakel S, Glatzel M, Seifert V, Kögel, D. Dietary Curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1, 2/STAT3 signaling pathway. Clin Cancer Res, 16: 5781-5795.
43. Eckert GP, Chang S, Eckmann J, Copanaki E, Hagl S, Hener U, Müller WE, Kögel D (2011). Liposome-incorporated DHA increases neuronal survival by enhancing non-amyloidogenic APP processing. BBA Biomembranes, 1808: 236-243.
44. Gessler F, Voss V, Seifert V, Gerlach R, Kögel D (2011). Knockdown of TFPI-2 promotes migration and invasion of glioma cells. Neurosci Lett.497: 49-54.
45. Bonner C, Farrelly AM, Concannon CG, Dussmann H, Baquié M, Virard I, Wobser H, Kögel D, Wollheim CB, Rupnik M, Byrne MM, König HG, Prehn JH (2011). Bone morphogenetic protein 3 controls insulin gene expression and is down-regulated in INS-1 cells inducibly expressing a hepatocyte nuclear factor 1A-maturity-onset diabetes of the young mutation. J Biol Chem. 286: 25719-25728.
46. Kögel D, Concannon CG, Müller T, König H, Bonner C, Poeschel S, Chang S, Egensperger R, Prehn JH. The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis. Neurobiol Aging. 2011 Jul 29. [Epub ahead of print]
(* both authors contributed equally to this work)
Reviews and Book Chapters
1. Kögel D, Prehn JH, Scheidtmann KH. (2001) The DAP kinase family of pro-apoptotic proteins: novel players in the apoptotic game. Bioessays 23: 352-358.
2. Kögel D, Prehn JH. (2002) Caspase-independent cell death mechanisms. In: Caspases - their role in cell death and cell survival, edited by M. Los & H. Walczak; Kluwer Press.
3. Prehn JH, Kögel D (2003). The self-destruction of neurons - physiological and pathophysiological decisions for the functional integrity. in: Brain damage and Repair. From molecular research to clinical therapy, edited by J.M. Delgado-Garcia and T. Herdegen, Kluwer Press.
4. Ward MW, Kögel D, Prehn JH. (2004) Neuronal apoptosis: BH3-only proteins the real killers? J Bioenerg Biomembr. 36: 295-298.
5. Rami A, Kögel D (2008). Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin?. Autophagy 4: 422-426.
6. Kögel D, Fulda S, Mittelbronn M (2010). Therapeutic exploitation of apoptosis and autophagy for glioblastoma. Anticancer Agents Med Chem. 10: 438-449.
7. Dützmann S, Gessler F, Harter PN, Gerlach R, Mittelbronn M, Seifert V, Kögel D (2010). The pro-migratory and pro-invasive role of the procoagulant tissue factor in malignant gliomas. Cell Adh Migr. 4: 515-522.
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