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Imbalance of intermediate filament component keratin 14 contributes to increased stress signalling in epidermolysis bullosa simplex
Author(s) -
Wagner Martin,
Trost Andrea,
Hintner Helmut,
Bauer Johann W.,
Onder Kamil
Publication year - 2013
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12112
Subject(s) - epidermolysis bullosa simplex , keratin 14 , microbiology and biotechnology , intermediate filament , signalling , kinase , keratin 5 , biology , keratin , cytoskeleton , genetics , cell , gene , transgene , genetically modified mouse
An important characteristic of epidermolysis bullosa simplex D owling– M eara ( EBS‐DM ) keratinocytes is the increased level of Jun N ‐terminal kinase ( JNK ) stress signalling, which is thought to contribute to the disease phenotype. In this work, we report on the dramatic up‐regulation of cytokeratin 14 ( K 14) in the EBS‐DM model cell line KEB 7 at both the transcriptional and translational levels, which is noteworthy because KEB 7 patient cells are heterozygous for a missense mutation ( R 125 P ) in K 14. By performing functional assays, we show a direct link between overexpressed wild‐type K 14 and increased JNK signalling in healthy, immortalized keratinocytes. This observation led us to hypothesize a positive feedback model in which mutant ( R 125 P ) K 14 triggers JNK signalling, leading to increased AP 1‐dependent expression of K 14, which in turn amplifies JNK signalling further. We therefore suggest that an imbalance of cytoplasmic K 14 monomers and K 14 incorporated into the intermediate filament ( IF ) network leads to elevated stress signalling, potentially altering IF dynamics by phosphorylation, which as a side effect, weakens EBS‐DM keratinocytes.