Within the lymphocyte lineage, GATA-3 is a major transcription factor implicated in the regulation of Th1/Th2 differentiation by promoting the expression of the Th2 cytokines, such as IL-4, IL-5, IL-10 and IL-13. Although the role of GATA-3 in the development of the Th2 lineage has been extensively described in the literature, the molecular mechanisms underlying its activity remain to be clarified. Here, we investigated whether GATA-3 might be regulated by reversible acetylation. In vivo, GATA-3 associates with class I and III HDACs. Biochemical studies unraveled the specific association of GATA-3 with the class III member SIRT1. Association with SIRT1 leads to the inhibition of GATA-3-induced IL-5 transcription. Using siRNA, we further show that SIRT1 promotes destabilization of GATA-3. Interestingly, nicotinamide, a specific inhibitor of SIRTs had no effect on the ability of SIRT1 to destabilize GATA-3 and to repress its transcriptional activity. In addition, a catalytic-defective mutant of SIRT1 (H363Y) shows similar effects to wild-type SIRT1, demonstrating that the deacetylase activity of SIRT1 is not required for its regulation of GATA-3. For the first time, our study indicates that SIRT1 is functionally linked to GATA-3. Moreover, our results also suggest that some important SIRT1 functions may not require its deacetylase activity.
| Identifer | oai:union.ndltd.org:BICfB/oai:ETDFUSAGx:FUSAGxetd-09292008-172304 |
| Date | 17 October 2008 |
| Creators | Mari, Nathalie |
| Contributors | Twizere, Jean-Claude, Théwis, André, kettmann, Richard, Dequiedt, Franck, Portetelle, Daniel, Wathelet, Bernard, Potente, M., Université de Francfort Allemagne |
| Publisher | Universite de Gembloux |
| Source Sets | Bibliothèque interuniversitaire de la Communauté française de Belgique |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://bictel-fusagx.ulg.ac.be/ETD-db/collection/available/FUSAGxetd-09292008-172304/ |
| Rights | restricted, Je certifie avoir complété et signé le contrat BICTEL/e remis par le gestionnaire facultaire. |
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