ArticleThe Journal of clinical investigation2017
A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 36 citations in OpenAlex.
- Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer.Clinical and translational medicine · 2025Article
- Readily releasable β cells with tight CaNature metabolism · 2024Article
- Functional screening and rational design of compounds targeting GPR132 to treat diabetes.Nature metabolism · 2023Article
- Functional screening and rational design of compounds targeting GPR132 to treat diabetes.Nature metabolism · 2023Article
- CRL4B complex-mediated H2AK119 monoubiquitination restrains Th1 and Th2 cell differentiation.Cell death and differentiation · 2023Article
- Cul5 mediates taurine-stimulated mTOR mRNA expression and proliferation of mouse mammary epithelial cells.Amino acids · 2023Article
- The Haematopoietically-expressed homeobox transcription factor: roles in development, physiology and disease.Frontiers in immunology · 2023Review
- Pancreatic α and β cells are globally phase-locked.Nature communications · 2022Article
- Urocortin3: Local inducer of somatostatin release and bellwether of beta cell maturity.Peptides · 2022Review
- lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus.Cell death and differentiation · 2022Article
- CUL4B is a Potential Novel Prognostic Biomarker and is Correlated with Immune Infiltrates in Malignant Pleural Mesothelioma.International journal of general medicine · 2022Article
- CUL4B Promotes Breast Carcinogenesis by Coordinating with Transcriptional Repressor Complexes in Response to Hypoxia Signaling Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
- δ-Cells: The Neighborhood Watch in the Islet Community.Biology · 2021Review
- Primary cilia control glucose homeostasis via islet paracrine interactions.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- In vitro expansion of pancreatic islet clusters facilitated by hormones and chemicals.Cell discovery · 2020Article
- Beta-Hydroxybutyrate Enhances BDNF Expression by Increasing H3K4me3 and Decreasing H2AK119ub in Hippocampal Neurons.Frontiers in neuroscience · 2020Article
- The functions and properties of cullin-5, a potential therapeutic target for cancers.American journal of translational research · 2020Review
- Cyclic AMP links glucose stimulation to somatostatin secretion in δ-cells.The Journal of general physiology · 2019Article
- Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular CaThe Journal of general physiology · 2019Article
- Deletion of pancreatic β-cell adenosine kinase improves glucose homeostasis in young mice and ameliorates streptozotocin-induced hyperglycaemia.Journal of cellular and molecular medicine · 2019Article
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Authors and funding
26 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Somatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion. Disruption of this circuit contributes to the development of diabetes. However, the precise mechanisms that control somatostatin secretion from islets remain elusive. Here, we found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets. Constitutive ablation of CUL4B, the core component of the CRL4B-PRC2 complex, in δ cells impaired glucose tolerance and decreased insulin secretion through enhanced somatostatin release. Moreover, mechanistic studies showed that the CRL4B-PRC2 complex, under the control of the δ cell-specific transcription factor hematopoietically expressed homeobox (HHEX), determines the levels of intracellular calcium and cAMP through histone posttranslational modifications, thereby altering expression of the Cav1.2 calcium channel and adenylyl cyclase 6 (AC6) and modulating somatostatin secretion. In response to high glucose levels or urocortin 3 (UCN3) stimulation, increased expression of cullin 4B (CUL4B) and the PRC2 subunit histone-lysine N-methyltransferase EZH2 and reciprocal decreases in Cav1.2 and AC6 expression were found to regulate somatostatin secretion. Our results reveal an epigenetic regulatory mechanism of δ cell paracrine interactions in which CRL4B-PRC2 complexes, Cav1.2, and AC6 expression fine-tune somatostatin secretion and facilitate glucose homeostasis in pancreatic islets.
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