Projects / Programmes source: ARIS

Regulation of gene expression and cell signaling in epidermolysis bullosa simplex: a hereditary skin fragility disorder with many faces

Research activity

Code Science Field Subfield
3.07.00  Medical sciences  Metabolic and hormonal disorders   

Code Science Field
B630  Biomedical sciences  Dermatology, venereology 

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
keratins, signaling, BCC, EBS, cell death, tumorigenesis
Evaluation (rules)
source: COBISS
Researchers (6)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  16104  PhD Apolonija Bedina Zavec  Biotechnology  Researcher  2010 - 2013  143 
2.  31814  Urška Dečko    Technical associate  2010 
3.  14305  PhD Mirjana Liović  Metabolic and hormonal disorders  Head  2010 - 2013  145 
4.  22580  PhD Špela Peternel  Biochemistry and molecular biology  Researcher  2011 - 2012  42 
5.  27742  PhD Alja Videtič Paska  Medical sciences  Researcher  2012  213 
6.  33509  Tina Zupančič  Biotechnology  Technical associate  2011 - 2013  25 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,277 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  45,364 
Amongst the large group of severe and often deadly skin fragility disorders called epidermolysis bullosa (EB), patients with the epidermolysis bullosa simplex Dowling-Meara type (EBS-DM) are more likely to develop basal cell carcinoma (BCC) than any other subtype. Interestingly it is the light-exposed areas of their skin that appear most often to give rise to BCCs. I showed that epithelial fragility in EBS-DM patients may be the result of the combined loss of keratin cytoskeleton function due to a keratin gene mutation (keratin 5 or 14), and the consequently decreased expression of many cell junction and cell adhesion proteins. At the same time this is also an advantage, as EBS-DM keratinocytes are faster at closing wounds than their control cells. Severe keratin mutations present an intrinsic physiological stress to cells as the MAPK stress response signaling pathways (JNK, ERK, p38) are constantly active in EBS-DM keratinocytes, thus also affecting major cellular processes. Therefore it appears that changes induced by keratin mutations in EBS-DM keratinocytes may be critical in directing them down a metabolic programme,which under certain circumstances may lead to non-melanoma skin cancer development. The proposed project aims to test and provide evidence for this hypothesis. To address this question we will analyze the metabolic differences between primary EBS-DM patient-derived and healthy, control keratinocytes, by using microarray analysis and comparing their expression profiles before and after exposure to a DNA damaging dose of gamma radiation. Our goal is to answer the following questions: (1) Can signaling triggered by mutant keratins affect NF-kB signaling? (2) Is the cell-death rate in keratin mutants altered in comparison to wild type keratinocytes? (3) Does the perpetually active stress response in severe EBS-DM mutants interfere with G1/S, G2/M checkpoints or (4) DNA repair mechanisms, and are any of these changes truly in the position to initiate cell transformation?
Significance for science
With the complete fulfilment of the aims and the research program of this grant we provided compelling evidence in support of our initial hypothesis regarding the exceptional role of the proteins (in this case keratins) that form the intermediate filament cytoskeleton in normal cell metabolism. We have shown that the consequences of severe keratin 5 or 14 gene mutations go beyond the simplistic view of keratins being only a structural support to cells. This study uncovers that keratins and keratin mutations may even alter the expression of proteins involved in the DNA damage stress response, cell cycle and regulation of cell death. Therefore it is quite plausible that such changes in cell metabolism may result with a higher incidence of basal cell carcinoma in the skin of epidermolysis bullosa simplex patients. This is truly original and novel data, which is of consequence not only for the field of molecular dermatology, but also for basic cell biology, by unveiling new knowledge about the cytoskeleton and the role of keratin intermediate filaments in cell metabolism. At the same time this data is already challenging us with a new question, whether keratins may be also a type of tumor suppressor?
Significance for the country
With our research data and the resulting scientific achievements, our participation at international conferences and the role in their organization, as well as our involvement in the function of European organizations, we actively contributed to a high impact image of Slovenian science and the Republic of Slovenia. In addition, our research has now presented a number of new potential targets for therapy development of a large family of currently still incurable genodermatoses, as well as challenged the scientific community with the possible new role of keratin proteins: not only as indicators of the process of transformation/stage of tumor growth, but also as the potential source of certain type of neoplastic changes.
Most important scientific results Annual report 2011, 2012, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2012, final report, complete report on dLib.si
Views history