| First Author | Gerst F | Year | 2015 |
| Journal | Diabetologia | Volume | 58 |
| Issue | 12 | Pages | 2819-31 |
| PubMed ID | 26363783 | Mgi Jnum | J:229038 |
| Mgi Id | MGI:5750262 | Doi | 10.1007/s00125-015-3744-z |
| Citation | Gerst F, et al. (2015) Protein kinase Cdelta regulates nuclear export of FOXO1 through phosphorylation of the chaperone 14-3-3zeta. Diabetologia 58(12):2819-31 |
| abstractText | AIMS/HYPOTHESIS: Forkhead box protein O1 (FOXO1) is a transcription factor essential for beta cell fate. Protein kinase B-dependent phosphorylation of FOXO1 at S256 (P-FOXO1) enables its binding to 14-3-3 dimers and nuclear export. Dephosphorylated FOXO1 enters nuclei and activates pro-apoptotic genes. Since our previous observations suggest that protein kinase C delta (PKCdelta) induces nuclear accumulation of FOXO1, the underlying mechanism was examined. METHODS: In human islets, genetically modified mice and INS-1E cells apoptosis was assessed by TUNEL staining. Subcellular translocation of proteins was examined by confocal microscopy and signalling pathways were analysed by western blotting and overlay assay. RESULTS: In PKCdelta-overexpressing (PKCdelta-tg) mouse islet cells and INS-1E cells FOXO1 accumulated in nuclei, surprisingly, as P-FOXO1. PKCdelta-tg decelerated IGF-1-dependent stimulation of nuclear export, indicating that changes in export caused nuclear retention of P-FOXO1. Nuclear accumulation of P-FOXO1 was accompanied by increased phosphorylation of 14-3-3zeta at S58 and reduced dimerisation of 14-3-3zeta. Palmitic acid further augmented phosphorylation of 14-3-3zeta and triggered nuclear accumulation of FOXO1 in both INS-1E and human islet cells. Furthermore, the overexpression of a phosphomimicking mutant of 14-3-3zeta (S58D) enhanced nuclear FOXO1. In accordance with the nuclear accumulation of P-FOXO1, PKCdelta overexpression alone did not increase apoptotic cell death. Additionally, insulin secretion and glucose homeostasis in PKCdelta-overexpressing mice remained unaffected. CONCLUSIONS/INTERPRETATION: These results suggest that PKCdelta-mediated phosphorylation of 14-3-3zeta contributes to the nuclear retention of FOXO1, even when FOXO1 is phosphorylated as under non-stress conditions. P-FOXO1 does not induce pro-apoptotic genes, but may rather exert beneficial effects on beta cells. |
