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. Author manuscript; available in PMC: 2015 Apr 23.
Published in final edited form as: Nature. 2014 Aug 20;514(7523):503–507. doi: 10.1038/nature13633

Extended Data Figure 9. FoxO1 regulatory network.

Extended Data Figure 9

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 (cyclinD1, cyclinD2) and inducing inhibitors (cdkn1a/p21, cdkn1b/p27, cdkn2b/p15Ink4b, cdkn1c/p57) [PMID: 10102273; PMID: 17873901]. cdkn1a/p21 and cdkn2b/p15Ink4b 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/p21 and cdkn1b/p27, 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]. PI3K/AKT/FoxO1 circuit requires active TGFβ/SMAD signaling [PMID: 24238962, PMID: 15084259] in order to co-regulate cdkn1a/p21-dependent cell senescence. Active TGFβ signaling downregulates the BMP pathway downstream effectors ID1 and ID2, known to promote dedifferentiation and proliferation during embryogenesis and cancer progression, probably through cdkn2b/p15Ink4b regulation [PMID: 11840321, PMID: 16034366]. b) β-cell ablation in adults triggers FoxO1 upregulation and the subsequent cell cycle arrest in δ-cells.