ArticleProceedings of the National Academy of Sciences of the United States of America2014
Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 97 citations in OpenAlex.
- MEF2D impairs mitochondrial respiration, glucose-stimulated insulin secretion, and survival in INS-1 β-cells.bioRxiv : the preprint server for biology · 2026Article
- Nr4a1 β-cell specific deletion impairs glucose tolerance in female mice.American journal of physiology. Endocrinology and metabolism · 2026Article
- Establishment of a mInternational journal of genomics · 2026Article
- Review
- NR4A1 Mediates Bronchopulmonary Dysplasia-Like Lung Injury Induced by Intrauterine Inflammation in Mouse Offspring.International journal of molecular sciences · 2025Article
- The universal role of adaptive transcription in health and disease.The FEBS journal · 2025Review
- Heterogeneous enhancer states orchestrate β cell responses to metabolic stress.Nature communications · 2024Article
- Loss of glucose-stimulated β-cell Nr4a1 expression impairs insulin secretion and glucose homeostasis.American journal of physiology. Cell physiology · 2024Article
- Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment.Current issues in molecular biology · 2024Review
- Article
- Analysis of an antioxidative defence system of hydrogen peroxide-treated pancreatic islet-derived 1.1B4 cells and siRNA targeting NR4A3-treated cells by microarray.Redox report : communications in free radical research · 2023Article
- Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic β-cell proliferation via phosphorylation of HDAC5.iScience · 2023Article
- Restored UBE2C expression in islets promotes β-cell regeneration in mice by ubiquitinating PER1.Cellular and molecular life sciences : CMLS · 2023Article
- Review
- Pancreatic islet cell type-specific transcriptomic changes during pregnancy and postpartum.iScience · 2023Article
- Hippo signaling and histone methylation control cardiomyocyte cell cycle re-entry through distinct transcriptional pathways.PloS one · 2023Article
- TEAD1 regulates cell proliferation through a pocket-independent transcription repression mechanism.Nucleic acids research · 2022Article
- Bioengineered Pancreas-Liver Crosstalk in a Microfluidic Coculture Chip Identifies Human Metabolic Response Signatures in Prediabetic Hyperglycemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- NR4A1 promotes LEF1 expression in the pathogenesis of papillary thyroid cancer.Cell death discovery · 2022Article
- Dihydroartemisinin alleviates AngII-induced vascular smooth muscle cell proliferation and inflammatory response by blocking the FTO/NR4A3 axis.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Loss of functional β-cell mass is a hallmark of type 1 and type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor NK6 homeobox 1 (Nkx6.1) in rat pancreatic islets induces β-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates β-cell expansion has not been defined. Here, we demonstrate that Nkx6.1 induces expression of the nuclear receptor subfamily 4, group A, members 1 and 3 (Nr4a1 and Nr4a3) orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in β-cell area in neonatal and young mice. Overexpression of Nkx6.1 and the Nr4a receptors results in increased expression of key cell cycle inducers E2F transcription factor 1 and cyclin E1. Furthermore, Nkx6.1 and Nr4a receptors induce components of the anaphase-promoting complex, including ubiquitin-conjugating enzyme E2C, resulting in degradation of the cell cycle inhibitor p21. These studies identify a unique bipartite pathway for activation of β-cell proliferation, suggesting several unique targets for expansion of functional β-cell mass.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.