Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/153607
Title: A cell-based drug discovery assay identifies inhibition of cell stress responses as a new approach to treatment of epidermolysis bullosa simplex
Authors: Tan, Tong San
Common, John E. A.
Lim, John S. Y.
Badowski, Cedric
Muhammad Jasrie Firdaus
Leonardi, Steven S.
Lane, E. Birgitte
Keywords: Science::Medicine
Issue Date: 2021
Source: Tan, T. S., Common, J. E. A., Lim, J. S. Y., Badowski, C., Muhammad Jasrie Firdaus, Leonardi, S. S. & Lane, E. B. (2021). A cell-based drug discovery assay identifies inhibition of cell stress responses as a new approach to treatment of epidermolysis bullosa simplex. Journal of Cell Science, 134(19), jcs258409-. https://dx.doi.org/10.1242/jcs.258409
Project: IAF311011
SPF2013/004
Journal: Journal of Cell Science
Abstract: In the skin fragility disorder epidermolysis bullosa simplex (EBS), mutations in keratin 14 (K14, also known as KRT14) or keratin 5 (K5, also known as KRT5) lead to keratinocyte rupture and skin blistering. Severe forms of EBS are associated with cytoplasmic protein aggregates, with elevated kinase activation of ERK1 and ERK2 (ERK1/2; also known as MAPK3 and MAPK1, respectively), suggesting intrinsic stress caused by misfolded keratin protein. Human keratinocyte EBS reporter cells stably expressing GFP-tagged EBS-mimetic mutant K14 were used to optimize a semi-automated system to quantify the effects of test compounds on keratin aggregates. Screening of a protein kinase inhibitor library identified several candidates that reduced aggregates and impacted on epidermal growth factor receptor (EGFR) signalling. EGF ligand exposure induced keratin aggregates in EBS reporter keratinocytes, which was reversible by EGFR inhibition. EBS keratinocytes treated with a known EGFR inhibitor, afatinib, were driven out of activation and towards quiescence with minimal cell death. Aggregate reduction was accompanied by denser keratin filament networks with enhanced intercellular cohesion and resilience, which when extrapolated to a whole tissue context would predict reduced epidermal fragility in EBS patients. This assay system provides a powerful tool for discovery and development of new pathway intervention therapeutic avenues for EBS.
URI: https://hdl.handle.net/10356/153607
ISSN: 0021-9533
DOI: 10.1242/jcs.258409
Rights: © 2021. Published by The Company of Biologists Ltd | Journal of Cell Science (2021). This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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