Keratin mutations of epidermolysis bullosa simplex alter the kinetics of stress response to osmotic shock

Mariella D'Alessandro, David Russell, Susan M. Morley, Anthony M. Davies, E. Birgitte Lane

    Research output: Contribution to journalArticle

    78 Citations (Scopus)

    Abstract

    The intermediate filament cytoskeleton is thought to confer physical resilience on tissue cells, on the basis of extrapolations from the phenotype of cell fragility that results from mutations in skin keratins. There is aneed for functional cell assays in which the impact of stress on intermediate filaments can be induced and analyzed. Using osmotic shock, we have induced cytoskeleton changes that suggest protective functions for actin and intermediate filament systems. Induction of the resulting stress response has been monitored in keratinocyte cells lines carrying K5 or K14 mutations, which are associated with varying severity of epidermolysis bullosa simplex. Cells with severe mutations were more sensitive to osmotic stress and took longer to recover from it. Their stress-activated response pathways were induced faster, as seen by early activation of JNK, ATF-2 and c-Jun. We demonstrate that the speed of a cell's response to hypotonic stress, by activation of the SAPK/JNK pathway, is correlated with the clinical severity of the mutation carried. The response to hypo-osmotic shock constitutes a discriminating stress assay to distinguish between the effects of different keratin mutations and is a potentially valuable tool in developing therapeutic strategies for keratin-based skin fragility disorders.
    Original languageEnglish
    Pages (from-to)4341-4351
    Number of pages11
    JournalJournal of Cell Science
    Volume115
    Issue number22
    DOIs
    Publication statusPublished - 2002

    Keywords

    • Epidermolysis bullosa simplex
    • Keratins
    • Keratinocyte cell lines
    • Osmotic shock
    • Stress response

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