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Hippo/Mst1 Stimulates Transcription of the Proapoptotic Mediator NOXA in a FoxO1-Dependent Manner

Publikace na Přírodovědecká fakulta |
2011

Tento text není v aktuálním jazyce dostupný. Zobrazuje se verze "en".Abstrakt

Previous studies of the cytotoxic effects of alpha-tocopheryl succinate (alpha-TOS) on cancer cells identified a mechanism whereby alpha-TOS caused apoptosis requiring the Noxa-Bak axis. In the present study, ab initio analysis revealed a conserved FoxO-binding site in the NOXA promoter, and specific affinity of FoxO proteins to this site was confirmed by fluorescence anisotropy.

FoxO1 and FoxO3a proteins accumulated in the nucleus of alpha-TOS-treated cells, and the specific FoxO1 association with the NOXA promoter and its activation were validated by chromatin immunoprecipitation. Using siRNA knockdown, a specific role for the FoxO1 protein in activating NOXA transcription was identified.

The proapoptotic kinase Hippo/Mst1 was found to be strongly activated by alpha-TOS, and inhibiting Hippo/Mst1 by specific siRNA prevented phosphorylation of FoxO1 and its nuclear translocation. Thus, alpha-TOS induce apoptosis by a mechanism involving the Hippo/Mst1-FoxO1-Noxa pathway.