Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/153607
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dc.contributor.authorTan, Tong Sanen_US
dc.contributor.authorCommon, John E. A.en_US
dc.contributor.authorLim, John S. Y.en_US
dc.contributor.authorBadowski, Cedricen_US
dc.contributor.authorMuhammad Jasrie Firdausen_US
dc.contributor.authorLeonardi, Steven S.en_US
dc.contributor.authorLane, E. Birgitteen_US
dc.date.accessioned2021-12-10T04:56:56Z-
dc.date.available2021-12-10T04:56:56Z-
dc.date.issued2021-
dc.identifier.citationTan, 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.258409en_US
dc.identifier.issn0021-9533en_US
dc.identifier.urihttps://hdl.handle.net/10356/153607-
dc.description.abstractIn 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.en_US
dc.language.isoenen_US
dc.relationIAF311011en_US
dc.relationSPF2013/004en_US
dc.relation.ispartofJournal of Cell Scienceen_US
dc.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 attributeden_US
dc.subjectScience::Medicineen_US
dc.titleA cell-based drug discovery assay identifies inhibition of cell stress responses as a new approach to treatment of epidermolysis bullosa simplexen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.contributor.organizationSkin Research Institute of Singapore, A*STARen_US
dc.contributor.organizationInstitute of Medical Biology, A*STARen_US
dc.identifier.doi10.1242/jcs.258409-
dc.description.versionPublished versionen_US
dc.identifier.pmid34643242-
dc.identifier.issue19en_US
dc.identifier.volume134en_US
dc.identifier.spagejcs258409en_US
dc.subject.keywordsEpidermolysis Bullosa Simplexen_US
dc.subject.keywordsEpidermolysis Bullosa Simplexen_US
dc.description.acknowledgementThis work was supported by DEBRA International grants LANE2/LANE3 to E.B.L., and by grants IAF311011 and SPF2013/004 to E.B.L. and J.E.A.C. from the Biomedical Research Council of Singapore. The funding sources were not involved in the conduct of the research, or writing of the manuscript. No payment was received from any pharmaceutical company or other for-profit agency to write the manuscript. Deposited in PMC for immediate release.en_US
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