|The role of proteases and protease inhibitors
in development and progression of cancer, immune processes and
and their inhibitors
play an important role in the normal function of cells and organisms.
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
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.
- 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 ß2 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.