Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner

0358947 - BTÚ 2011 RIV US eng J - Článek v odborném periodiku
Vališ, Karel - Procházka, L. - Bouřa, Evžen - Chladová, Jaromíra - Obšil, T. - Rohlena, Jakub - Truksa, Jaroslav - Dong, L.F. - Ralph, S.J. - Neužil, Jiří
Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner.
Cancer Research. Roč. 71, č. 3 (2011), s. 946-954. ISSN 0008-5472. E-ISSN 1538-7445
Grant CEP: GA AV ČR(CZ) KJB500970904; GA ČR(CZ) GA204/08/0811; GA AV ČR(CZ) IAA500520702; GA ČR GAP301/10/1937
Výzkumný záměr: CEZ:AV0Z50520701; CEZ:AV0Z50110509
Klíčová slova: Mst1 kinase * FoxO proteins * alpha-tocopheryl succinate
Kód oboru RIV: FD - Onkologie a hematologie
Impakt faktor: 7.856, rok: 2011

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
Trvalý link: http://hdl.handle.net/11104/0196844