The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53
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Volume
10
Publisher
DOI
10.1038/s41419-019-1988-0
Journal
CELL DEATH & DISEASE
ISSN
2041-4889
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Show full item recordAbstract
Desmoglein-3 (Dsg3), the Pemphigus Vulgaris (PV) antigen (PVA), plays an essential role in keratinocyte cell–cell
adhesion and regulates various signaling pathways involved in the progression and metastasis of cancer where it is
upregulated. We show here that expression of Dsg3 impacts on the expression and function of p53, a key transcription
factor governing the responses to cellular stress. Dsg3 depletion increased p53 expression and activity, an effect
enhanced by treating cells with UVB, mechanical stress and genotoxic drugs, whilst increased Dsg3 expression
resulted in the opposite effects. Such a pathway in the negative regulation of p53 by Dsg3 was Dsg3 specific since
neither E-cadherin nor desmoplakin knockdown caused similar effects. Analysis of Dsg3−/− mouse skin also indicated
an increase of p53/p21WAF1/CIP1 and cleaved caspase-3 relative to Dsg3+/− controls. Finally, we evaluated whether this
pathway was operational in the autoimmune disease PV in which Dsg3 serves as a major antigen involved in blistering
pathogenesis. We uncovered increased p53 with diffuse cytoplasmic and/or nuclear staining in the oral mucosa of
patients, including cells surrounding blisters and the pre-lesional regions. This finding was verified by in vitro studies
where treatment of keratinocytes with PV sera, as well as a characterized pathogenic antibody specifically targeting
Dsg3, evoked pronounced p53 expression and activity accompanied by disruption of cell–cell adhesion. Collectively,
our findings sugg
Authors
Rehman, A; Cai, Y; Huenefeld, C; Jedlickova, H; Huang, Y; Teh, MT; Ahmad, US; Uttagomol, J; Wang, Y; Kang, ACollections
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