department of biotechnology
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The role of proteases and protease inhibitors in development and progression of cancer, immune processes and neurodegenerative diseases:

Proteases and their inhibitors play an important role in the normal function of cells and organisms. In immune processes their role is crucial in antigen presentation, cell cytotoxicity, phagocytosis and activation and proliferation of most immune cells.  Our group  is investigating the role of cysteine proteases and associated factors in the maturation of dendritic cells, and the activation and functioning of T lymphocytes and cells of innate immunity, such as macrophages and NK cells.
We demonstrated that some proteases may cause changes in cell signalling, adhesion and migration as a consequence of gradual degradation of integrin receptors. This activity re-modulates the cell cytoskeleton and causes the formation of cell extensions, uropods and nanotubes, enabling new modes of signalling including the transfer of cytoplasmic vesicles. Protease inhibitors may regulate these processes.
Proteases are important also for the proper functioning of neuron cells. Their uncontrolled action is associated with neurodegenerative diseases, in this case protease inhibitors can be promising agents for the treatment of patients. In this field we investigate the role of cathepsins in the regulation of neurotrophic activity of gamma enolase. Important are also the results, achieved in collaboration with partners in UK, explaining the role of mutations in protein FUS, which are associated with the cause of familial amyotrophic lateral sclerosis type 6.
Degradation of extracellular matrix is an important step in the development and progression of cancer the, leading to increased invasiveness and metastasis of tumour cells. Proteases participate in this process, both intra- and extra-cellularly. We showed that protease inhibitors, capable of inhibiting protease activity at both sites, effectively impair the invasiveness of tumour cells. Our work is focused on investigating the molecular mechanisms of these processes in tumour cells, identification of proteases as targets for anti-tumour therapy and of inhibitors as potential anti-tumour drugs.

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Selected publications:

  • Kocbek, Petra, Obermajer, Nataša, Cegnar, Mateja, Kos, Janko, Kristl, Julijana. Targeting cancer cells using PLGA nanoparticles surface modified with monoclonal antibody. J. control. release. , 2007, iss. 1-2, vol. 120, str. 18-26.
  • Jevnikar, Zala, Obermajer, Nataša, Bogyo, Matthew, Kos, Janko. The role of cathepsin X in the migration and invasiveness of T lymphocytes. J Cell Sci, 2008, issue 16, vol. 121, str. 2652-2661.
  • Obermajer, Nataša, Jevnikar, Zala, Doljak, Bojan, Sadaghiani, A. M., Bogyo, Matthew, Kos, Janko. Cathepsin X-mediated 2 integrin activation results in nanotube outgrowth. Cell Mol Life Sci (Print. ed.), 2009, no. 6, vol. 66, str. 1126-1134.
  • Obermajer, Nataša, Doljak, Bojan, Kos, Janko. Cytokeratin 8 ectoplasmic domain binds urokinase-type plasminogen activator to breast tumor cells and modulates their adhesion, growth and invasiveness. Mol Cancer, 2009, vol. 8, no. 88, 31 str.
  • Vance, Caroline, Rogelj, Boris in sod. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis Type 6. Science (Wash. D.C.), 2009, vol. 323, no. 5918, str. 1208-1211.

    Contact:
    Janko Kos
    trak ang