desmosomes Dotaz Zobrazit nápovědu
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 suggest a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, and this pathway is disrupted in PV.
- MeSH
- desmoglein 3 nedostatek metabolismus MeSH
- desmozomy metabolismus MeSH
- fyziologický stres * MeSH
- kaspasa 3 metabolismus MeSH
- keratinocyty metabolismus MeSH
- kultivované buňky MeSH
- kůže metabolismus MeSH
- leupeptiny farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- pemfigus krev imunologie patologie MeSH
- proteolýza MeSH
- protilátky imunologie MeSH
- psi MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The continuously growing rodent incisor is an emerging model for the study of renewal of mineralized tissues by adult stem cells. Although the Bmp, Fgf, Shh, and Wnt pathways have been studied in this organ previously, relatively little is known about the role of Notch signaling during incisor renewal. Notch signaling components are expressed in enamel-forming ameloblasts and the underlying stratum intermedium (SI), which suggested distinct roles in incisor renewal and enamel mineralization. Here, we injected adult mice with inhibitory antibodies against several components of the Notch pathway. This blockade led to defects in the interaction between ameloblasts and the SI cells, which ultimately affected enamel formation. Furthermore, Notch signaling inhibition led to the downregulation of desmosome-specific proteins such as PERP and desmoplakin, consistent with the importance of desmosomes in the integrity of ameloblast-SI attachment and enamel formation. Together, our data demonstrate that Notch signaling is critical for proper enamel formation during incisor renewal, in part by regulating desmosome-specific components, and that the mouse incisor provides a model system to dissect Jag-Notch signaling mechanisms in the context of mineralized tissue renewal.
- MeSH
- ameloblasty metabolismus patologie MeSH
- desmozomy metabolismus patologie MeSH
- myši MeSH
- nemoci zubů MeSH
- receptory Notch * MeSH
- řezáky metabolismus patologie MeSH
- signální transdukce * MeSH
- zubní sklovina metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- chrupavka cytologie embryologie MeSH
- desmozomy embryologie MeSH
- metakarpus embryologie MeSH
- ovce MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Klíčová slova
- tonofibrily,
- MeSH
- alergická kontaktní dermatitida MeSH
- desmozomy ultrastruktura MeSH
- krotonový olej škodlivé účinky MeSH
Autoři uvádějí sestavu tří pacientek léčených pro extraabdominální desmoid za posledních 12 let na Ortopedické klinice FN v Hradci Králové.Věk první byl 27 let, zbývající dvě byly třicetileté. Mírná bolestivost měkkotkáňového tumoru byla při doteku nebo aktivním pohybu. Lokalizace nádoru byla jednou V oblasti zad a dvakrát v oblasti ramena. Z předoperačních vyšetření je počítáno s rtgmímky v základních projekcích a s ultrazvukem. Je vhodné doplnit ještě CT-vyšetřením vypovídajícím přesněji o vztahu tumoru k okolním tkáním. Nejdůležitější pro stanovení diagnózy je histologické vyŠetření, kde zejména u proliferujících variant bývá odlišení od fibrosarkomu obtížné. Vždy bylo provedeno chirurgické léčení, a to široká excize tumoru do zdravé tkáně. Jediný tento výkon stačil k vyléčení pacientky č. 2. Velká tendence nádoru k místním recidívam si vyžádala u zbývajících dvou opakované reoperace, u pacientky č. 3 byla aplikována při větším počtu recidív i aktinoterapie. V diskusi jsou zmiňovány vlivy hormonální a trauma, které se podle literárních údaju mohou uplatňovat v etiologii tohoto poměrně vzácného onemocnění, postihujícího převážně ženy fertilního věku. Dlouhodobá předpověď je velmi dobrá a s přibývajícím věkem jsou recidívy vzácnější.
The authors present a group of three female patients treated on account of an extraabdominal desmoid during the last 12 years at the Orthopaedic Clinic of the Faculty Hospital in Hradec Králové.The age of one patient was 27 years, the others were 30 years old. They reported mild pain of the soft tissue tumour on touch or during active movement. The tumour was in one instance in the area of the back and twice in the area of the shoulder. Preoperative examinations include X-ray pictures in the basic projections and ultrasound. It is useful to supplement them by CT examination which gives more detailed information on the relationship of the tumour and surrounding tissues. Most important for establishment of the diagnosis is histological examination where in particular in proliferating varieties the differentiation from fibrosarcoma is difficult. In all instances treatment was by surgery, i. e. Wide excision of the tumour into sound tissue. This procedure alone was sufficient in patient no. 2. The marked tendency of local relapses of the tumour called in the remaining two patients for repeated reoperations, in patient no. 3 after several relapses actinotherapy was used. In the discussion the authors mention hormonal influences and injuries which according to data in the literature can play a part in the etiology of this relatively rare disease'affecting mainly women in fertile age. The long-term prognosis is very favourable and with advancing age relapses are less frequent.
- Klíčová slova
- rohová vrstva,
- MeSH
- desmozomy fyziologie ultrastruktura MeSH
- epidermální buňky MeSH
- epidermis * anatomie a histologie MeSH
- kůže * anatomie a histologie cytologie MeSH
- lidé MeSH
- lipidy * analýza MeSH
- Check Tag
- lidé MeSH
