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Keratin gene mutations influence the keratinocyte response to DNA damage and cytokine induced apoptosis
National Institute of Chemistry, Ljubljana.
Institute of Oncology, Ljubljana.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
A*Star Institute of Medical Biology, Singapore.
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2017 (English)In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 309, no 7, 587-593 p.Article in journal (Refereed) Published
Abstract [en]

The keratin filament cytoskeleton is vital to the normal function of epithelial cells. It provides structural support and regulates different aspects of cell metabolism. Mutations in keratins 5 and 14 cause a skin fragility disorder, epidermolysis bullosa simplex (EBS). Patients with severe EBS have an increased cumulative risk for basal cell carcinoma. In this study, we tested how keratin 5 and 14 mutant EBS patient-derived keratinocytes behave in the face of two different types of stressors that are able to induce cell death: ionizing radiation and cytokines TNF-alpha and TRAIL. The data point out to a substantial difference between how normal and keratin mutant keratinocytes deal with such stresses. When case of DNA damage, the ATM/Chk2-pathway is one of the two main tracks that can prevent the progression of mitosis and so allow repair. This was altered in all investigated keratin mutants with a particular down-regulation of the activated form of checkpoint kinase 2 (pChk2). Keratin mutants also appear less sensitive than normal cells to treatment with TNF-alpha or TRAIL, and this may be linked to the up-regulation of two pro-survival proteins, Bcl-2 and FLIP. Such changes are likely to have a profound effect on mutant keratinocytes ability to survive and withstand stress, and in theory this may be also a contributing factor to cell transformation.

Place, publisher, year, edition, pages
2017. Vol. 309, no 7, 587-593 p.
Keyword [en]
Keratin, Mutation, DNA damage, Chk2, Apoptosis, Keratinocyte
National Category
Dermatology and Venereal Diseases
Identifiers
URN: urn:nbn:se:uu:diva-334920DOI: 10.1007/s00403-017-1757-9ISI: 000408716700010OAI: oai:DiVA.org:uu-334920DiVA: diva2:1161205
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2017-11-29Bibliographically approved

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Törmä, Hans

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