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Projects / Programmes source: ARIS

Role of cysteine cathepsins in regulation of cell proliferation and cell death

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Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
P310  Natural sciences and mathematics  Proteins, enzymology 
Keywords
Proteases; cysteine cathepsins; cell death; apoptosis; proliferation; cancer; functional genomics; chemogenomics; proteomics; bioimaging
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (7)
no. Code Name and surname Research area Role Period No. of publications
1.  23572  PhD Lea Bojič  Pharmacy  Researcher  2008  35 
2.  18801  PhD Marko Fonović  Biochemistry and molecular biology  Researcher  2008 - 2011  187 
3.  24261  PhD Saška Ivanova  Biochemistry and molecular biology  Researcher  2009  35 
4.  25642  PhD Urška Požgan  Pharmacy  Researcher  2010 - 2011  24 
5.  29542  PhD Barbara Sobotič  Biochemistry and molecular biology  Junior researcher  2008 - 2011  62 
6.  07561  PhD Boris Turk  Biochemistry and molecular biology  Head  2008 - 2011  1,037 
7.  21619  PhD Olga Vasiljeva  Oncology  Researcher  2008 - 2011  183 
Organisations (1)
no. Code Research organisation City Registration number No. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,706 
Abstract
Many physiological processes, including tissue development and homeostasis, require a balance between cell death and cell proliferation, whereas even slight imbalance of the system may stimulate proliferation of the cell, facilitating the cell's oncogenic transformation. There is considerable evidence for the involvement of lysosomal cysteine peptidases, primarily cathepsins B and L, in cell proliferation and cell death. However, the precise role of cysteine cathepsins in control mechanisms determining cell-fate remains unclear and requires a systematic approach including cathepsin-deficient cells. Thus, fibroblasts deficient in individual cysteine cathepsin and tumor cells obtained from genetically modified mice will enable us to perform a critical experimental evaluation of cathepsins importance for cell proliferation and cell death. In addition, this should enable a better understanding of the molecular mechanisms of cathepsins involvement in cell cycle regulation, thereby validating their role as potentially relevant targets for cancer treatment. In order to obtain comprehensive information on the underlying molecular mechanisms, the proteins that are differentially regulated in absence and normal presence of the lysosomal peptidases in primary mouse embryonic fibroblasts and primary tumor cells will be determined by proteome analyses. Finally, the functional imaging of proteases will be performed in vitro and in cell cultures, providing a rationale for evaluation of cysteine cathepsins as valid target for drug design in cancer treatment.
Significance for science
The main goal of the project was to determine the role of cysteine cathepsins in the regulation of balance between cell proliferation and programmed cell death. Since even slight disruption of that balance may stimulate cells proliferation facilitating their oncogenic transformation, the obtained results of the project will be of great importance for the basic science as well as for the validation the role of cysteine cathepsins as relevant targets for cancer treatment. Furthermore, the systematic study employing cathepsins depleted fibroblasts and tumor cells derived from knockout mice with deficiencies for the respective cathepsins, as well as tumor cell lines helped us to address the impact of specific proteases for the process of apoptosis. A long-term goal of the project is to unravel the role of cysteine cathepsins in tumor progression and to establish whether the cathepsins are valid target for drug design in cancer treatment, to enable testing of potential new therapeutics. This project has also broadened the research at the Department of Biochemistry and Molecular and Structural Biology at Jožef Stefan Institute in the field of cell and cancer biology and represents an important step towards possible use of cathepsin inhibitors in cancer treatment.
Significance for the country
Proteases are currently one of the major targets for new therapeutics. Numerous experimental and clinical researches proposed the use of protease inhibitors in cancer treatment. Thus, the obtained results of this project will have a great importance in evaluation of cysteine cathepsins as possible therapeutic targets in cancer. This research and further use of representative animal cancer models are therefore extremely valuable tools and of high value for the evaluation of compounds on preclinical level, which should be interesting for the pharmaceutical companies present in Slovenia. This is also one of the long-term goals of the project. Similar connections have already been established in past, as seen from the numerous contracts in past. Although the project was more basic research, it also had its applied component and can be classified as strategic basic research. As can be seen, members of the group have extensively collaborated with Slovene industry (Lek, Krka), which resulted in a substantial amount of contract-based research. The work also offered great opportunity for students to be trained in the most advanced methods and areas, such as proteomics, which has been established at the IJS within the group, and chemogenomics together with European and other international partners. Both fields have namely high international priority as they are of extreme importance in target identification and validation during drug development. This has reflected also on the doctoral work done within the project, as well as on the works of other graduate students that is linked with the topic of the project. In addition, members of the project have received wide-spread international recognition which is very important for the world-wide promotion of Slovenia and as such also for preservation of national identity of Slovenia.
Most important scientific results Annual report 2008, 2009, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2008, 2009, final report, complete report on dLib.si
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