biostudies-literatureTomiyasu HCanon Medical Systems Corporation Tokyo CL SquareJapan Science and Technology Agency Fusion Oriented REsearch for disruptive Science and TechnologyJapan Society for the Promotion of Science107209https://www.ebi.ac.uk/biostudies/studies/S-EPMC11021968biostudies-literatureUnknown300(4)FOXO1 is a transcription factor and potential tumor suppressor that is negatively regulated downstream of PI3K-PKB/AKT signaling. Paradoxically, FOXO also promotes tumor growth, but the detailed mechanisms behind this role of FOXO are not fully understood. In this study, we revealed a molecular cascade by which the Thr24 residue of FOXO1 is phosphorylated by AKT and is dephosphorylated by calcineurin, which is a Ca²⁺-dependent protein phosphatase. Curiously, single nucleotide somatic mutations of FOXO1 in cancer occur frequently at and near Thr24. Using a calcineurin inhibitor and shRNA directed against calcineurin, we revealed that calcineurin-mediated dephosphorylation of Thr24 regulates FOXO1 protein stability. We also found that FOXO1 binds to the promoter region of MDM2 andThe Journal of biological chemistryFOXO1 promotes cancer cell growth through MDM2-mediated p53 degradation.PMC11021968S22-004720K2150321H02403JPMJFR2065Hanaki STomiyasu HHabara MShimada MSato YMiki YfalseFOXO1 promotes cancer cell growth through MDM2-mediated p53 degradation.FOXO1 is a transcription factor and potential tumor suppressor that is negatively regulated downstream of PI3K-PKB/AKT signaling. Paradoxically, FOXO also promotes tumor growth, but the detailed mechanisms behind this role of FOXO are not fully understood. In this study, we revealed a molecular cascade by which the Thr24 residue of FOXO1 is phosphorylated by AKT and is dephosphorylated by calcineurin, which is a Ca²⁺-dependent protein phosphatase. Curiously, single nucleotide somatic mutations of FOXO1 in cancer occur frequently at and near Thr24. Using a calcineurin inhibitor and shRNA directed against calcineurin, we revealed that calcineurin-mediated dephosphorylation of Thr24 regulates FOXO1 protein stability. We also found that FOXO1 binds to the promoter region of MDM2 and2024-01-01T00:00:00Z2024 Apr2026-06-01T18:59:36.476Z2026-05-19T03:07:01.518ZS-EPMC110219683851902910.1016/j.jbc.2024.107209