Dual-specificity phosphatases in the hypo-osmotic stress response of keratin-defective epithelial cell lines

Mirjana Liovic, Brian Lee, Marjana Tomic-Canic, Mariella D'Alessandro, Viacheslav N Bolshakov, E Birgitte Lane

    Research output: Contribution to journalArticlepeer-review

    28 Citations (Scopus)

    Abstract

    Although mutations in intermediate filament proteins cause many human disorders, the detailed pathogenic mechanisms and the way these mutations affect cell metabolism are unclear. In this study, selected keratin mutations were analysed for their effect on the epidermal stress response. Expression profiles of two keratin-mutant cell lines from epidermolysis bullosa simplex patients (one severe and one mild) were compared to a control keratinocyte line before and after challenge with hypo-osmotic shock, a common physiological stress that transiently distorts cell shape. Fewer changes in gene expression were found in cells with the severely disruptive mutation (55 genes altered) than with the mild mutation (174 genes) or the wild type cells (261 genes) possibly due to stress response pre-activation in these cells. We identified 16 immediate-early genes contributing to a general cell response to hypo-osmotic shock, and 20 genes with an altered expression pattern in the mutant keratin lines only. A number of dual-specificity phosphatases (MKP-1, MKP-2, MKP-3, MKP-5 and hVH3) are differentially regulated in these cells, and their downstream targets p-ERK and p-p38 are significantly up-regulated in the mutant keratin lines. Our findings strengthen the case for the expression of mutant keratin proteins inducing physiological stress, and this intrinsic stress may affect the cell responses to secondary stresses in patients' skin.
    Original languageEnglish
    Pages (from-to)2066-2075
    Number of pages10
    JournalExperimental Cell Research
    Volume314
    Issue number10
    DOIs
    Publication statusPublished - 2008

    Keywords

    • Animals
    • Cell Line
    • Dual-Specificity Phosphatases
    • Epidermolysis Bullosa Simplex
    • Epithelial Cells
    • Gene Expression Profiling
    • Gene Expression Regulation, Enzymologic
    • Humans
    • Keratins
    • Mutation
    • Oligonucleotide Array Sequence Analysis
    • Osmolar Concentration
    • Osmotic Pressure

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