14-3-3 proteins are essential signalling hubs for beta cell survival

Lim, Gareth E.; Piske, Micah; Johnson, James D.

doi:10.1007/s00125-012-2820-x

Cited by 46 publications

(59 citation statements)

References 49 publications

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“…a 38 kDa protein which bound the PKCδ antibody). Cytosolic 14-3-3ζ has been found to bind to BAD and BAX, inhibiting their pro-apoptotic action [22]. Our data suggest that nuclear 14-3-3ζ binds to P-FOXO1, thereby promoting nuclear extrusion of the transcription factor.…”

Section: Discussionmentioning

confidence: 65%

“…Our data suggest that nuclear 14-3-3ζ binds to P-FOXO1, thereby promoting nuclear extrusion of the transcription factor. This additional role underlines the importance of 14-3-3ζ for beta cell function and explains why INS-1E cells do not survive after small interfering RNA-mediated downregulation of 14-3-3ζ (own observations and [22]). …”

Section: Discussionmentioning

confidence: 80%

“…PKCδ phosphorylates 14-3-3ζ at S58 and impairs its dimerisation The chaperone 14-3-3ζ is highly expressed in beta cells and its dimerisation is impaired by phosphorylation at S58, which is also a phosphorylation site of PKCδ [22,35,36]. Since nuclear export of FOXO1 requires binding of P-FOXO1 to 14-3-3 dimers [19], we used an overlay assay to examine the interaction between the immunoprecipitated FOXO1 and HRP-labelled 14-3-3ζ (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our results suggest that the nuclear export is decelerated due to PKCδ-dependent phosphorylation and impaired dimerisation of 14-3-3ζ. Of the seven 14-3-3 isoforms expressed in beta cells, 14-3-3ζ is a target of PKCδ [22,36]. Indeed, nuclear P-S58-14-3-3ζ was increased in PKCδ-tg INS-1E cells and its levels were further augmented by palmitate.…”

Section: Discussionmentioning

confidence: 97%

“…In beta cells, 14-3-3ζ is highly expressed and sequesters the pro-apoptotic proteins BAD and BAX in the cytosol. In accordance, reduced levels of 14-3-3ζ induce mitochondrial-linked beta cell death [22].…”

Section: Introductionmentioning

confidence: 84%

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Protein kinase Cδ regulates nuclear export of FOXO1 through phosphorylation of the chaperone 14-3-3ζ

et al. 2015

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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 (PKCδ) 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 PKCδ-overexpressing (PKCδ-tg) mouse islet cells and INS-1E cells FOXO1 accumulated in nuclei, surprisingly, as P-FOXO1. PKCδ-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 14-3-3ζ at S58 and reduced dimerisation of 14-3-3ζ. Palmitic acid further augmented phosphorylation of 14-3-3ζ and triggered nuclear accumulation of FOXO1 in both INS-1E and human islet cells. Furthermore, the overexpression of a phosphomimicking mutant of 14-3-3ζ (S58D) enhanced nuclear FOXO1. In accordance with the nuclear accumulation of P-FOXO1, PKCδ overexpression alone did not increase apoptotic cell death. Additionally, insulin secretion and glucose homeostasis in PKCδ-overexpressing mice remained unaffected. Conclusions/interpretation These results suggest that PKCδ-mediated phosphorylation of 14-3-3ζ 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.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 80%