The desmosomal cadherin desmoglein-3 acts as a keratinocyte
anti-stress protein via suppression of p53

J 2019

The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53

REHMAN, A; Y CAI; C HUNEFELD; Hana JEDLIČKOVÁ; YY HUANG et al.

Základní údaje

Originální název

The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53

Autoři

REHMAN, A; Y CAI; C HUNEFELD; Hana JEDLIČKOVÁ; YY HUANG; MT TEH; US AHMAD; J UTTAGOMOL; Y WANG; A KANG; G WARNES; C HARWOOD; D BERGAMASCHI; EK PARKINSON; M ROCKEN a H WAN

Vydání

CELL DEATH & DISEASE, LONDON, NATURE PUBLISHING GROUP, 2019, 2041-4889

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.304

Označené pro přenos do RIV

Organizační jednotka

Lékařská fakulta

DOI

https://doi.org/10.1038/s41419-019-1988-0

UT WoS

000488856200011

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 27. 10. 2020 13:41, Mgr. Tereza Miškechová

Anotace

V originále

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/p21(WAF1/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 suggest a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, and this pathway is disrupted in PV.

Citovat

REHMAN, A; Y CAI; C HUNEFELD; Hana JEDLIČKOVÁ; YY HUANG; MT TEH; US AHMAD; J UTTAGOMOL; Y WANG; A KANG; G WARNES; C HARWOOD; D BERGAMASCHI; EK PARKINSON; M ROCKEN a H WAN. The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53. CELL DEATH & DISEASE. LONDON: NATURE PUBLISHING GROUP, 2019, roč. 10, OCT 2019, s. 1-14. ISSN 2041-4889. Dostupné z: https://doi.org/10.1038/s41419-019-1988-0.

@article{1687457,
   author = {Rehman, A and Cai, Y and Hunefeld, C and Jedličková, Hana and Huang, YY and Teh, MT and Ahmad, US and Uttagomol, J and Wang, Y and Kang, A and Warnes, G and Harwood, C and Bergamaschi, D and Parkinson, EK and Rocken, M and Wan, H},
   article_location = {LONDON},
   article_number = {OCT 2019},
   doi = {https://doi.org/10.1038/s41419-019-1988-0},
   language = {eng},
   issn = {2041-4889},
   journal = {CELL DEATH & DISEASE},
   note = {Bez afiliace k MU},
   title = {The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53},
   url = {https://www.nature.com/articles/s41419-019-1988-0.pdf},
   volume = {10},
   year = {2019}
}

TY  - JOUR
ID  - 1687457
AU  - Rehman, A - Cai, Y - Hunefeld, C - Jedličková, Hana - Huang, YY - Teh, MT - Ahmad, US - Uttagomol, J - Wang, Y - Kang, A - Warnes, G - Harwood, C - Bergamaschi, D - Parkinson, EK - Rocken, M - Wan, H
PY  - 2019
TI  - The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53
JF  - CELL DEATH & DISEASE
VL  - 10
IS  - OCT 2019
SP  - 1-14
EP  - 1-14
PB  - NATURE PUBLISHING GROUP
SN  - 20414889
N1  - Bez afiliace k MU
UR  - https://www.nature.com/articles/s41419-019-1988-0.pdf
N2  - 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/p21(WAF1/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 suggest a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, and this pathway is disrupted in PV.
ER  -

REHMAN, A; Y CAI; C HUNEFELD; Hana JEDLIČKOVÁ; YY HUANG; MT TEH; US AHMAD; J UTTAGOMOL; Y WANG; A KANG; G WARNES; C HARWOOD; D BERGAMASCHI; EK PARKINSON; M ROCKEN a H WAN. The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53. \textit{CELL DEATH \&{}amp; DISEASE}. LONDON: NATURE PUBLISHING GROUP, 2019, roč.~10, OCT 2019, s.~1-14. ISSN~2041-4889. Dostupné z: https://doi.org/10.1038/s41419-019-1988-0.

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