Dokument: The role of lipid rafts in UVA radiation-induced signal transduction in human keratinocytes
| Titel: | The role of lipid rafts in UVA radiation-induced signal transduction in human keratinocytes | |||||||
| Weiterer Titel: | The role of lipid rafts in UVA radiation-induced signal transduction in human keratinocytes | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=13972 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20100202-115817-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dr.rer.net Walli, Rehab [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Priv.-Doz.. Dr.rer.nat Grether-Beck Susanne [Gutachter] Prof. Dr. Proksch Peter [Gutachter] | |||||||
| Stichwörter: | UVA Rafts Keratinocytes Skin | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Solar ultraviolet A (UVA; 320-400 nm) radiation in physiological doses is able to induce gene expression in human skin. There is increasing evidence that UVA radiation plays an important role in the pathogenesis of the most frequent photodermatoses, polymorphic light eruption as well as in photoaging and photocarcinogenesis. Human epidermal keratinocytes represent the primary cellular target for UVA radiation. Ceramide generation within membrane microdomains enriched in cholesterol and glycosphingolipids (lipid rafts) on the cell surface participate in the signal transduction pathway operative in UVA-induced gene expression. In this work we report that in addition to the degradation of sphingomyelin also the degradation of glycosphinglipids e.g. GM3 contributes to ceramide formation in rafts observed upon UVA treatment. The degradation of GM3, the main glycosphingolipid in keratinocytes, was found to be mediated via the raft associated, ganglioside specific sialidase called neuraminidase 3. Degradation of gangliosides was of functional relevance for UVA signaling and significantly contributed to the UVA response, because inhibiting neuraminidase 3 activation resulted in a subsequent inhibition of the downstream signaling elements which are (i) UVA-induced Src kinase activation, (ii) caveolin-1 phosphorylation, (iii) AP-2 activation, and (iv) finally ICAM-1 upregulation.
As expected for a raft associated enzyme, cholesterol loading decreased enzyme activity, whereas cholesterol decrease via beta-methylcyclodextrin treatment increased neuraminidase 3 activity. Furthermore, the singlet oxygen quencher vitamin E inhibited UVA induced neuraminidase 3 activity. As neuraminidase 3 closely associates with caveolin-1, the caveolae stabilizing and cholesterol binding protein, we found that depletion of caveolin-1 by retrovirus-mediated RNA interference abolished the capacity of human keratinocytes to further increase neuraminidase 3 activity. The composition of cholesterol, sphingolipids and glycosphingolipids critically controls the function of rafts. UVA responsiveness of the cells is determined by the ratio of these components in lipid rafts. In particular, the ratio of ceramide versus cholesterol determines the responsiveness towards UVA radiation. Our results indicate that depletion of caveolin-1 rendered keratinocytes resistant towards UVA-induced ceramide formation und the subsequent signaling events such as activation of Src kinase and AP-2, and upregulation of ICAM-1. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie | |||||||
| Dokument erstellt am: | 01.02.2010 | |||||||
| Dateien geändert am: | 01.02.2010 | |||||||
| Promotionsantrag am: | 27.03.2006 | |||||||
| Datum der Promotion: | 25.01.2010 |
