ArticleDiabetologia2013
14-3-3 proteins are essential signalling hubs for beta cell survival.
Article in Diabetologia, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 52 citations in OpenAlex.
- Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbAScientific reports · 2017Pooled it
- A high-throughput screening approach to discover potential colorectal cancer chemotherapeutics: repurposing drugs to identify novel disruptors of 14-3-3 proteins.Cell death & disease · 2025Article
- Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.Nature communications · 2025Article
- Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.bioRxiv : the preprint server for biology · 2024Article
- 14-3-3 binding motif phosphorylation disrupts Hdac4-organized condensates to stimulate cardiac reprogramming.Cell reports · 2024Article
- Article
- Is 14-3-3 the Combination to Unlock New Pathways to Improve Metabolic Homeostasis and β-Cell Function?Diabetes · 2023Review
- Cotransplantation of marginal mass allogeneic islets with 3D culture-derived adult human skin cells improves glycemia in diabetic mice.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2023Article
- 14-3-3-zeta mediates GLP-1 receptor agonist action to alter α cell proglucagon processing.Science advances · 2022Article
- 14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells.JCI insight · 2022Article
- Cellular Stress Responses in Oocytes: Molecular Changes and Clinical Implications.Advances in experimental medicine and biology · 2022Review
- 14-3-3ζ mediates an alternative, non-thermogenic mechanism in male mice to reduce heat loss and improve cold tolerance.Molecular metabolism · 2020Article
- Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data.Genome medicine · 2019Article
- Proteomic changes in oocytes after in vitro maturation in lipotoxic conditions are different from those in cumulus cells.Scientific reports · 2019Article
- Scaffold Proteins: From Coordinating Signaling Pathways to Metabolic Regulation.Endocrinology · 2018Review
- Elucidation of the 14-3-3ζ interactome reveals critical roles of RNA-splicing factors during adipogenesis.The Journal of biological chemistry · 2018Article
- Plasticity in the Glucagon Interactome Reveals Novel Proteins That Regulate Glucagon Secretion in α-TC1-6 Cells.Frontiers in endocrinology · 2018Article
- Article
- Protein kinase Cδ regulates nuclear export of FOXO1 through phosphorylation of the chaperone 14-3-3ζ.Diabetologia · 2015Article
- Changes in Brain 14-3-3 Proteins in Response to Insulin Resistance Induced by a High Palatable Diet.Molecular neurobiology · 2015Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
aims/hypothesisDiabetes is characterised by pancreatic beta cell death and dysfunction, resulting from unbalanced pro-survival and pro-death signalling. The 14-3-3 proteins are molecular adaptors that integrate numerous signalling pathways, including the v-raf-leukaemia viral oncogene 1 (RAF1)/B cell leukaemia/lymphoma 2 (BCL-2)-associated agonist of cell death (BAD) pathway, which we have previously implicated in insulin-dependent beta cell survival. Nevertheless, the roles of 14-3-3 proteins in beta cell fate and function have not been investigated.
methodsWe examined the abundance, localisation, modulation and roles of 14-3-3 proteins using quantitative RT-PCR, immunoblot or imaging. MIN6 cells or mouse islets cells were manipulated with inhibitors, short interfering RNA (siRNA) or plasmids overexpressing 14-3-3.
resultsWe first characterised the abundance and subcellular location of all seven 14-3-3 isoforms in mouse and human beta cells. Most isoforms were cytoplasmic, except 14-3-3σ, which appeared to be nuclear. Analysis of 14-3-3 abundance under stress conditions revealed distinct modulation in mouse islets and MIN6 cells. Generalised 14-3-3 inhibition promoted apoptosis and dysfunction, and siRNA-mediated knockdown revealed isoform-specific roles in caspase-3-dependent beta cell apoptosis, with a clear role for 14-3-3ζ. Overabundance of 14-3-3ζ sequestered BAD-BCL2-associated X protein (BAX) from mitochondria, attenuated Dp5 (also known as Hrk) and Puma (also known as Bbc3) induction, and increased survival in response to pro-inflammatory cytokines or thapsigargin. Anti-apoptotic insulin treatment increased the sequestration of BAD/BAX by 14-3-3ζ. BAD mutants that were unable to bind 14-3-3ζ localised to mitochondria and induced apoptosis. CONCLUSIONS/
interpretationThis first study of the 14-3-3 family in beta cells revealed specific regulation, localisation and anti-apoptotic roles among the isoforms. Focus on 14-3-3ζ revealed its importance in preventing BAD-BAX mitochondrial localisation and protecting beta cells from multiple stresses. Thus, some 14-3-3 proteins are pro-survival signalling hubs.
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