Anmerkungen:
Tag der Verteidigung: 27.02.2024
Zusammenfassungen in deutscher und englischer Sprache
Beschreibung:
FoxO3a (Fork-head box O3a) is a transcription factor that regulates various cellular processes such as stress resistance, metabolism, cell-cycle arrest, and apoptosis. Modulation of stress responses by FoxO3a contributes to longevity in model organisms, such as C. elegans. Based on functional analogy and common interacting partners like β-catenin and Smad3, we speculated that Nit1 (Nitrilase1) might interact with FoxO3a and thereby regulate its function. Indeed, we observed the complex formation of Nit1 and FoxO3a in co-immunoprecipitation and proximity ligation assays. Moreover, pull-down assays with purified recombinant proteins confirmed the direct binding of Nit1 and FoxO3a. Interestingly, this interaction was modified upon exposure to varying concentrations of hydrogen peroxide (H2O2). Furthermore, β-catenin dissociates Nit1/FoxO3a complex. In addition, in reporter gene assays we observed that both wild-type FoxO3a and a dominant-active FoxO3a (T32A, S253A, S315A) mutant transcriptionally upregulate Nit1 expression suggesting a feedback regulatory mechanism. To investigate the physiological role of Nit1 we analyzed its ortholog nft-1 (NitFhit) in C. elegans. nft-1 knockout worms displayed a longer lifespan compared to wild-type worms, suggesting a repressive role of nft-1 in this respect.