Extended Data Figure 9: FoxO1 regulatory network.
From: Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers
a, Cartoon depicting the FoxO1 network involved in the regulation of cell cycle progression and cellular senescence: FoxO1 arrests the cell cycle by repressing activators (cyclin D1, cyclin D2) and inducing inhibitors (Cdkn1a, Cdkn1b, Cdkn2b, Cdkn1c) (PMID: 10102273; PMID: 17873901). Cdkn1a and Cdkn2b activation, a sign of cellular senescence (PMID: 17667954), is regulated by FoxO1 through direct interaction with Skp2 protein. In turn, Skp2 blocks FoxO1 and, together with CKS1b, CDK1 and CDK2, triggers the direct degradation of Cdkn1a and Cdkn1b, thus promoting proliferation (PMID: 15668399). FoxO proteins are inhibited mainly through PI3K/AKT-mediated phosphorylation (PMID: 10102273; PMID: 12621150; PMID: 21708191; PMID: 10217147; PMID: 17604717]: PDK1, the master kinase of the pathway, stimulates cell proliferation and survival by directly activating AKT, which phosphorylates (inhibits) the FoxOs (PMID: 10698680; PMID: 19635472). The PI3K/AKT/FoxO1 circuit requires active TGF-β/SMAD signalling (PMID: 24238962; PMID: 15084259) in order to co-regulate Cdkn1a-dependent cell senescence. Active TGF-β signalling downregulates the BMP pathway downstream effectors ID1 and ID2, known to promote dedifferentiation and proliferation during embryogenesis and cancer progression, probably through Cdkn2b regulation (PMID: 11840321; PMID: 16034366). b, β-cell ablation in adults triggers FoxO1 upregulation and the subsequent cell cycle arrest in δ-cells.
