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.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• alfa-katenin metabolismus   MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• autoprotilátky krev   imunologie   metabolismus   MeSH
• buněčná adheze účinky léků   imunologie   MeSH
• buněčné linie MeSH
• desmoglein 3 imunologie   metabolismus   MeSH
• genový knockdown MeSH
• keratinocyty MeSH
• lidé MeSH
• MAP kinasový signální systém účinky léků   imunologie   MeSH
• oxidační stres účinky léků   imunologie   MeSH
• pemfigus krev   farmakoterapie   imunologie   patologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• studie případů a kontrol MeSH
• transkripční faktory genetika   metabolismus   MeSH
• ústní sliznice imunologie   patologie   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, α-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• aktivní transport - buněčné jádro * MeSH
• alfa-katenin metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• buňky A549 MeSH
• cytoplazma metabolismus   MeSH
• fosfoproteiny metabolismus   MeSH
• fosforylace MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• kadheriny metabolismus   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• myši nahé MeSH
• myši MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protein dishevelled metabolismus   MeSH
• protein Wnt1 metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• proteiny Wnt metabolismus   MeSH
• transport proteinů MeSH
• tumor supresorové geny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials.

• MeSH
• adenokarcinom genetika   patologie   MeSH
• alfa-katenin genetika   MeSH
• celogenomová asociační studie * MeSH
• duktální karcinom pankreatu genetika   patologie   MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• přežití po terapii bez příznaků nemoci MeSH
• prognóza MeSH
• protein PEBP2alfaA genetika   MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH