The Division of Molecular Biology of the Department of Surgery was established in 1999 and is headed by Wolfgang Dubiel. Research is focused on the elucidation of structure and function of the COP9 signalosome (CSN) and its role in the ubiquitin proteasome system (UPS). The CSN is associated with kinases, which phosphorylate transcription factors such as c-Jun and p53 (see figure) influencing their ubiquitination and subsequent degradation. Phosphorylation of c-Jun stabilizes the transcription factor towards the UPS. In contrast, CSN-mediated phosphorylation of p53 targets the tumor suppressor to degradation by the 26S proteasome. Inhibitors of CSN-associated kinases such as curcumin and curcumin-like substances destabilize c-Jun and increase p53 levels, which reduces tumor angiogenesis and might be useful in tumor therapy. In addition, the CSN is associated with the deubiquitinating enzyme USP15, which is responsible for the protection of ubiquitin ligase components. The CSN possesses an intrinsic metalloprotease activity that removes Nedd8 from cullins. Cycles of deneddylation and neddylation regulate the activity of cullin-RING ubiquitin ligases. Ubiquitin ligation determines substrate specificity in the ubiquitin system, the major proteolytic pathway in eukaryotic cells. Its function as a regulator of ubiquitin ligases makes the CSN a potential target for clinical application.

[b2]

Functional cooperation between COP9 signalosome and 26S proteasome

Clinical research

Previous and current research:

• The CSN as a therapeutic target: Role of the signalosome/proteasome system in [b3] tumor angiogenesis. Curcumin, an inhibitor of CSN-associated kinases, suppresses VEGF production in tumor cells.
• Curcumin as an inhibitor of tubulogenesis in the matrigel assay, HIV-Tat protein derived peptides as activators of tubulogenesis.
• Taurolidine, an anti-tumor drug, inhibits protein biosynthesis in mammalian cells and in bacteria.
• Identification and characterization of curcumin-like and emodin-like compounds that block CSN-associated kinases and are potential inhibitors of tumor angiogenesis.
• The stability of COX-2, an important regulator of tumor angiogenesis, is controlled by the CSN.

Future projects and goals:

• The impact of curcumin- and emodin-like substances on apoptosis in tumor cells and on tubulogenesis, examination of selected compounds in animal tumor models.
• Characterization of taurolidine and taurolidine-like compounds as inhibitors of tumor angiogenesis.
• Interplay between beta-catenin, APC, EB1 and the CSN and the impact on tumor angiogenesis.
• Studies on the role of CSN-mediated deneddylation and deubiquitination in human disease.

Selected publications:

1. Pollmann, C.; Huang, X.; Mall, J.; Bech-Otschir, D.; Naumann, M.; Dubiel, W. The constitutive photomorphogenesis 9 signalosome directs vascular endothelial growth factor production in tumor cells. Cancer Res., 2001, 61, 8416-8421.
2. Braumann, C.; Henke, W.; Jacobi, C.A.; Dubiel, W. The tumor-suppressive reagent taurolidine is an inhibitor of protein biosynthesis. Int. J. Cancer, 2004, 112, 225-230.
3. Fullbeck, M.; Huang, X.; Dumdey, R.; Frommel, C.; Dubiel, W.; Preissner, R. Novel curcumin- and emodin-related compounds identified by in silico 2D/3D conformer screening induce apoptosis in tumor cells. BMC Cancer, 2005, 5, 97.
4. Ismail, M.; Henklein, P.; Huang, X.; Braumann, C.; Ruckert, R.I.; Dubiel, W. Identification of HIV-1 Tat peptides for future therapeutic angiogenesis. Eur. J. Haematol., 2006, 77, 157-165.
5. Neuss, H.; Huang, X.; Hetfeld, B.K.J.; Deva, R.; Henklein, P.; Nigam, S.; Mall, J.W.; Schwenk, W.; Dubiel, W. The ubiquitin-and proteasome-dependent degradation of COX-2 is regulated by the COP9 signalosome and differentially influenced by coxibs. J. Mol. Med., 2007, 85(9), 961-970. Epub 2007 Apr 11.
6. Braumann, C.; Tangermann, J.; Jacobi, C.A.; Müller, J.M.; Dubiel, W. Novel anti-angiogenic compounds for application in tumor therapy - COP9 signalosome-associated kinases as possible targets. Mini-Rev Med Chem., 2008, 8(5), 421-428.

[b4]Basic research

Previous and current research:

• Interactions of CSN subunits and the architecture of the CSN and the 26S proteasome lid.
• At the crossroads of signal transduction and proteolysis: Studies on molecular mechanism and biological function of the signalosome/proteasome system.
• The CSN is associated with the kinases CK2 and PKD that modify c-Jun, p53 as well as p27 and determine the stability of the proteins.
• The CSN is associated with the deubiquitinating enzyme USP15 that protects components of ubiquitin ligases from autoubiquitination and degradation.
• The CSN as a regulator of the UPS: Studies on the interaction of the CSN with cullin-RING ubiquitin ligases and with the 26S proteasome. The formation of "super-complexes".
• The CSN controls the degradation of the microtubule end-binding protein 1, EB1, via the UPS. Putative E3s and consequences for microtubule function.

Future projects and goals:

• Impact of specific siRNA oligos against subunits of the CSN on the structure and function of the complex.
• Studies on the function and the assembly/disassembly of "super-complexes" consisting of the CSN, cullin-RING ubiquitin ligases and the proteasome.
• Regulation of the assembly of the CSN in mammalian cells.
• The network of neddylation/deneddylation and ubiquitination/deubiquitination. Function of the ubiquitin family (UbF) protein Nedd8 in the regulation of ubiquitination by E3s. The role of the CSN-mediated deneddylation.

Selected publications:

1. Kapelari, B.; Bech-Otschir, D.; Hegerl, R.; Schade, R.; Dumdey, R.; Dubiel, W. Electron microscopy and subunit-subunit interaction studies reveal a first architecture of COP9 signalosome. J. Mol. Biol., 2000, 300, 1169-1178.
2. Bech-Otschir, D.; Kraft, R.; Huang, X.; Henklein, P.; Kapelari, B.; Pollmann, C.; Dubiel, W. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J., 2001, 20, 1630-1639.
3. Uhle, S.; Medalia, O.; Waldron, R.; Dumdey, R.; Henklein, P.; Bech-Otschir, D.; Huang, X.; Berse, M.; Sperling, J.; Schade, R.; Dubiel, W. Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome. EMBO J., 2003, 22, 1302-1312.
4. Berse, M.; Bounpheng, M.; Huang, X.; Christy, B.; Pollmann, C.; Dubiel, W. Ubiquitin-dependent Degradation of Id1 and Id3 is Mediated by the COP9 Signalosome. J. Mol. Biol., 2004, 343, 361-370.
5. Bech-Otschir, D.; Kapelari, B.; Dubiel, W. The COP9 Signalosome: Its Possible Role in the Ubiquitin System. In Protein Degradation, Volume 1: Ubiquitin and the Chemistry of Life, R. Mayer; A. Ciechanover; M. Rechsteiner, eds. (Weinheim: WILEY-VCH Verlag GmbH & Co. KGaA), 2005; 348-369.
6. Hetfeld, B.K.; Helfrich, A.; Kapelari, B.; Scheel, H.; Hofmann, K.; Guterman, A.; Glickman, M.; Schade, R.; Kloetzel, P.M.; Dubiel, W. The zinc finger of the CSN-associated deubiquitinating enzyme USP15 is essential to rescue the E3 ligase Rbx1. Curr. Biol., 2005, 15, 1217-1221.
7. Huang, X.; Hetfeld, B.K.; Seifert, U.; Kahne, T.; Kloetzel, P.M.; Naumann, M.; Bech-Otschir, D.; Dubiel, W. Consequences of COP9 signalosome and 26S proteasome interaction. Febs J, 2005, 272, 3909-3917.
8. Huang, X.; Wagner, E.; Dumdey, R.; Peth, A.; Berse, M.; Dubiel, W.; Berndt, C. Phosphorylation by COP9 signalosome-associated CK2 promotes degradation of p27 during the G1 cell cycle phase. Isr. J. Chem., 2006, 46, 231-238.
9. Peth, A.; Boettcher, J.P.; Dubiel, W. Ubiquitin-dependent Proteolysis of the Microtubule End-binding Protein 1, EB1, Is Controlled by the COP9 Signalosome: Possible Consequences for Microtubule Filament Stability. J. Mol. Biol., 2007, 368, 550-563.
10. Hetfeld, B.K.; Peth, A.; Sun, X.M.; Henklein, P.; Cohen, G.M.; Dubiel, W. The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis. Apoptosis, 2008, 13(2), 187-195.[b5]

People

Current members of the lab:

[b7]

Alumni, former members of the lab:

Surgeons who temporary worked in the lab: