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@ARTICLE{Homberg:189847,
author = {Homberg, Melanie and Ramms, Lena and Schwarz, Nicole and
Dreissen, Georg and Leube, Rudolf and Merkel, Rudolf and
Hoffmann, Bernd and Magin, Thomas M.},
title = {{D}istinct impact of two keratin mutations causing
epidermolysis bullosa simplex on keratinocyte adhesion and
stiffness},
journal = {The journal of investigative dermatology},
volume = {135},
number = {000},
issn = {0022-202X},
address = {Basingstoke [u.a.]},
publisher = {Nature Publishing Group},
reportid = {FZJ-2015-02853},
pages = {2437–2445},
year = {2015},
abstract = {Keratin filaments constitute the major component of the
epidermal cytoskeleton from heterodimers of type I and type
II keratin subunits. Missense mutations in keratin 5 or
keratin 14, highly expressed in the basal epidermis, cause
the severe skin blistering disease epidermolysis bullosa
simplex (EBS) in humans by rendering the keratin
cytoskeleton sensitive to mechanical stress; yet, the
mechanisms by which individual mutations cause cell
fragility are incompletely understood. Here, we compared the
K14p.Arg125Pro with the K5p.Glu477Asp mutation, both giving
rise to severe generalized EBS, by stable expression in
keratin-free keratinocytes. This revealed distinctly
different effects on keratin cytoskeletal organization, in
agreement with in vivo observations, thus validating the
cell system. Although the K14p.Arg125Pro mutation led to
impaired desmosomes, downregulation of desmosomal proteins,
and weakened epithelial sheet integrity upon shear stress,
the K5p.Glu477Asp mutation did not impair these functions,
although causing EBS with squamous cell carcinoma in vivo.
Atomic force microscopy demonstrated that K14 mutant cells
were even less resistant against deformation compared with
keratin-free keratinocytes. Thus, a keratin mutation causing
EBS compromises cell stiffness to a greater extent than the
lack of keratins. Finally, re-expression of K14 in K14
mutant cells did not rescue the above defects. Collectively,
our findings have implications for EBS therapy approaches.},
cin = {ICS-7},
ddc = {610},
cid = {I:(DE-Juel1)ICS-7-20110106},
pnm = {552 - Engineering Cell Function (POF3-552)},
pid = {G:(DE-HGF)POF3-552},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000360995600016},
pubmed = {pmid:25961909},
doi = {10.1038/jid.2015.184},
url = {https://juser.fz-juelich.de/record/189847},
}