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

Rehman, Ambreen; Cai, Yuepiao; Hünefeld, Christian; Jedličková, Hana; Huang, Yunying; Teh, Muy-Teck; Ahmad, Usama Sharif; Uttagomol, Jutamas; Wang, Ying; Kang, Angray S.; Warnes, Gary; Harwood, Catherine A.; Bergamaschi, Daniele; Parkinson, Eric Kenneth; Röcken, Martin; Wan, Hong

doi:10.1038/s41419-019-1988-0

Cited by 25 publications

(60 citation statements)

References 48 publications

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“…PV sera were obtained from 10 patients; all with informed patient consent and local ethical approval by the Institutional Ethics Committees. The pathogenic activities of PV sera were characterized in keratinocytes in our recent report (37).…”

Section: Cell Lines Pv Sera and Clinical Patient Oral Mucosal Samplesmentioning

confidence: 99%

“…Non-neoplastic lines N/TERT (derived from the skin) and OKF4 (derived from oral mucosa) used in the study were immortalized normal human keratinocyte cell lines (39,40) and were maintained in keratinocyte serum-free medium (KSFM) (17005042, Thermo Scientific). For the experiments, in general cells were seeded at approximately 70~80% confluent densities in KSFM for one day before cultured in complete keratinocyte growth medium (KGM) (37). Cells treated with PV sera including dose-and time course experiments, were cultured in calcium-containing (1.2~1.8mM) KSFM for different time periods.…”

Section: Keratinocyte Culture and Treatmentmentioning

confidence: 99%

“…The heat-induced epitope retrieval method was used with antigen retrieval buffer EDTA kit (pH=9, Zsbio, China: http://www.zsbio.com/cmsstatic/documents/product/ZLI-9079. pdf), the same method described in our previous report (37). Specifically, slides were transferred to the pressure cooker after boiling.…”

Section: Immunohistochemistry In Pv Specimensmentioning

confidence: 99%

“…In brief, 2x10 6 cells were seeded into a 100 mm dish overnight and then were transfected with either scrambled or specific siRNA at a final concentration of 50 nM in KSFM using DharmaFECT 1(T-2001-02, Dharmacon) following the manufacturer's instructions. The next day, cells were harvested with 0.25% Trypsin/EDTA and re-plated at approximately 70~80% confluent densities for Western blotting or immunofluorescence analysis as described previously (29,37).…”

Section: Yap Sirna Transfectionmentioning

confidence: 99%

“…Furthermore, YAP has been implicated in regulating antioxidant gene expression via complexing with transcription factor FoxO1 and its inactivation by Hippo signaling suppresses FoxO1 activity and decreases antioxidant gene expression (26). In light of our recent findings that 1) Dsg3 exerts a function as an anti-stress protein via suppression of p53, ROS and apoptosis and 2) Dsg3 plays a role in regulating YAP (29,37,38), we hypothesized that altered YAP caused by oxidative stress might occur in PV. We report here that PV-IgG targeting Dsg3 provoked transient ROS overproduction accompanied by YAP dysregulation, leading to altered cell-cell adhesion and ultimately, blistering.…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Stress-Mediated YAP Dysregulation Contributes to the Pathogenesis of Pemphigus Vulgaris

et al. 2021

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Pemphigus Vulgaris (PV) is a life-threatening autoimmune disease manifested with blisters in the skin and mucosa and caused by autoantibodies against adhesion protein desmoglein-3 (Dsg3) expressed in epithelial membrane linings of these tissues. Despite many studies, the pathogenesis of PV remains incompletely understood. Recently we have shown Dsg3 plays a role in regulating the yes-associated protein (YAP), a co-transcription factor and mechanical sensor, and constraining reactive oxygen species (ROS). This study investigated the effect of PV sera as well as the anti-Dsg3 antibody AK23 on these molecules. We detected elevated YAP steady-state protein levels in PV cells surrounding blisters and perilesional regions and in keratinocytes treated with PV sera and AK23 with concomitant transient ROS overproduction. Cells treated with hydrogen peroxide also exhibited augmented nuclear YAP accompanied by reduction of Dsg3 and α-catenin, a negative regulator of YAP. As expected, transfection of α-catenin-GFP plasmid rendered YAP export from the nucleus evoked by hydrogen peroxide. In addition, suppression of total YAP was observed in hydrogen peroxide treated cells exposed to antioxidants with enhanced cell-cell adhesion being confirmed by decreased fragmentation in the dispase assay compared to hydrogen peroxide treatment alone. On the other hand, the expression of exogenous YAP disrupted intercellular junction assembly. In contrast, YAP depletion resulted in an inverse effect with augmented expression of junction assembly proteins, including Dsg3 and α-catenin capable of abolishing the effect of AK23 on Dsg3 expression. Finally, inhibition of other kinase pathways, including p38MAPK, also demonstrated suppression of YAP induced by hydrogen peroxide. Furthermore, antioxidant treatment of keratinocytes suppressed PV sera-induced total YAP accumulation. In conclusion, this study suggests that oxidative stress coupled with YAP dysregulation attributes to PV blistering, implying antioxidants may be beneficial in the treatment of PV.

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Section: Cell Lines Pv Sera and Clinical Patient Oral Mucosal Samplesmentioning

confidence: 99%

Section: Keratinocyte Culture and Treatmentmentioning

confidence: 99%

Section: Immunohistochemistry In Pv Specimensmentioning

confidence: 99%

Section: Yap Sirna Transfectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oxidative Stress-Mediated YAP Dysregulation Contributes to the Pathogenesis of Pemphigus Vulgaris

et al. 2021

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Desmoglein‐3 induces YAP phosphorylation and inactivation during collective migration of oral carcinoma cells

2022

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Alterations of the Hippo–YAP pathway are potential targets for oral squamous cell carcinoma (OSCC) therapy, but heterogeneity in this pathway could be responsible for therapeutic resistance. We analysed the Hippo–YAP signatures in a cohort of characterised keratinocyte cell lines derived from the mouth floor and buccal mucosa from different stages of OSCC tumour progression and focused on the specific role of YAP on invasive and metastatic potential. We confirmed heterogeneity in the Hippo–YAP pathway in OSCC lines, including overexpression of YAP1, WWTR1 (often referred to as TAZ) and the major Hippo signalling components, as well as the variations in the genes encoding the intercellular anchoring junctional proteins, which could potentially regulate the Hippo pathway. Specifically, desmoglein‐3 (DSG3) exhibited a unique and mutually exclusive regulation of YAP via YAP phosphorylation during the collective migration of OSCC cells. Mechanistically, such regulation was associated with inhibition of phosphorylation of epidermal growth factor receptor (EGFR) (S695/Y1086) and its downstream effectors heat shock protein beta‐1 (Hsp27) (S78/S82) and transcription factor AP‐1 (c‐Jun) (S63), leading to YAP phosphorylation coupled with its cytoplasmic translocation and inactivation. Additionally, OSCC lines displayed distinct phenotypes of YAP dependency or a mixed YAP and TAZ dependency for cell migration and present distinct patterns in YAP abundance and activity, with the latter being associated with YAP nuclear localisation. In conclusion, this study provides evidence for a newly identified paradigm in the Hippo–YAP pathway and suggests a new regulation mechanism involved in the control of collective migration in OSCC cells.

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Mutant TP53 promotes invasion of lung cancer cells by regulating desmoglein 3

Feng,

Qian,

Cui

et al. 2024

J Cancer Res Clin Oncol

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Purpose Targeted therapies have markedly improved the prognosis of lung cancer patients; nevertheless, challenges persist, including limited beneficiary populations and the emergence of drug resistance. This study investigates the molecular mechanisms of mutant TP53 in lung cancer, aiming to contribute to novel strategies for targeted therapy. Methods The TCGA database was employed to delineate the mutational landscape of TP53 in lung cancer patients. Differential gene expression between TP53-mutant and wild-type patients was analyzed, followed by functional enrichment. DSG3 protein expression in lung cancer patients was assessed using IHC, and its impact on prognosis was analyzed in the TCGA database. The influence of TP53 on the downstream gene DSG3 was investigated using qPCR, ChIP-qPCR, and luciferase reporter gene assays. Protein enrichment in the DSG3 promoter region was examined through IP-MS, and the regulatory role of the HIF1-α/TP53 complex on DSG3 was explored using Co-IP, luciferase assays, and ChIP-qPCR. Molecular interactions between TP53 (R273H) and HIF1-α were detected through immunoprecipitation and molecular docking. The effects and mechanisms of DSG3 on lung cancer phenotypes were assessed through WB, transwell, and wound healing assays. Results TP53 mutations were present in 47.44% of patients, predominantly as missense mutations. DSG3 exhibited high expression in TP53-mutant lung cancer patients, and this elevated expression correlated with a poorer prognosis. TP53 interference led to a reduction in DSG3 mRNA expression, with TP53 mutant P53 enriching at the P2 site of the DSG3 promoter region, a recruitment facilitated by HIF1-α. The DBD region of TP53 (R273H) demonstrated interaction with HIF1-α. DSG3, activated through Ezrin phosphorylation, played a role in promoting invasion and metastasis. Conclusions Mutant TP53 facilitates lung cancer cell invasion by modulating desmoglein 3. Graphical abstract

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

Cited by 25 publications

References 48 publications

Oxidative Stress-Mediated YAP Dysregulation Contributes to the Pathogenesis of Pemphigus Vulgaris

Oxidative Stress-Mediated YAP Dysregulation Contributes to the Pathogenesis of Pemphigus Vulgaris

Desmoglein‐3 induces YAP phosphorylation and inactivation during collective migration of oral carcinoma cells

Mutant TP53 promotes invasion of lung cancer cells by regulating desmoglein 3

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