ArticleDiabetes2010
Absence of p53-dependent apoptosis combined with nonhomologous end-joining deficiency leads to a severe diabetic phenotype in mice.
Article in Diabetes, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
- Genetics of type 2 diabetes: Beyond single nucleotide variant studies.Molecular metabolism · 2026Review
- Single-cell RNA-seq and in vitro study reveal Fusobacterium nucleatum impairs β-cell identity in type 2 diabetes via the NF-κB-CDKN1C axis.Journal of translational medicine · 2026Article
- Insulin production is sustained during DNA damage-mediated senescence in adult human beta cells.Diabetologia · 2026Article
- Targeting p53-p21 signaling to enhance mesenchymal stem cell regenerative potential.Regenerative therapy · 2025Review
- Safeguarding genomic integrity in beta-cells: implications for beta-cell differentiation, growth, and dysfunction.Biochemical Society transactions · 2024Review
- Analyzing Amylin Aggregation Inhibition Through Quantum Dot Fluorescence Imaging.International journal of molecular sciences · 2024Article
- Identification of hub genes and pathways associated with cellular senescence in diabetic foot ulcers via comprehensive transcriptome analysis.Journal of cellular and molecular medicine · 2024Article
- Pancreatic β-cell senescence in diabetes: mechanisms, markers and therapies.Frontiers in endocrinology · 2023Review
- Failure to repair endogenous DNA damage in β-cells causes adult-onset diabetes in mice.Aging biology · 2023Article
- DNA damage to β cells in culture recapitulates features of senescent β cells that accumulate in type 1 diabetes.Molecular metabolism · 2022Article
- NF90-NF45 is essential for β cell compensation under obesity-inducing metabolic stress through suppression of p53 signaling pathway.Scientific reports · 2022Article
- Inhibition of USP7 suppresses advanced glycation end-induced cell cycle arrest and senescence of human umbilical vein endothelial cells through ubiquitination of p53.Acta biochimica et biophysica Sinica · 2022Article
- TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell.Metabolites · 2021Article
- Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1Metabolism: clinical and experimental · 2021Article
- Senescence and Type 2 Diabetic Cardiomyopathy: How Young Can You Die of Old Age?Frontiers in pharmacology · 2021Review
- Article
- Ileal Transposition Increases Pancreatic β Cell Mass and Decreases β Cell Senescence in Diet-Induced Obese Rats.Obesity surgery · 2020Article
- Schizandrin A Protects Human Retinal Pigment Epithelial Cell Line ARPE-19 against HG-Induced Cell Injury by Regulation of miR-145.Molecular therapy. Nucleic acids · 2020Article
- Rapid generation and selection of Cas9-engineering TRP53 R172P mice that do not have off-target effects.BMC biotechnology · 2019Article
- Dual Role of Nitric Oxide in Regulating the Response of β Cells to DNA Damage.Antioxidants & redox signaling · 2018Review
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
objectiveRegulation of pancreatic beta-cell mass is essential to preserve sufficient insulin levels for the maintenance of glucose homeostasis. Previously, we reported that DNA double-strand breaks (DSBs) resulting from nonhomologous end-joining (NHEJ) deficiency induce apoptosis and, when combined with p53 deficiency, progressed rapidly into lymphomagenesis in mice. Combination of NHEJ deficiency with a hypomorphic mutation, p53R172P, leads to the abrogation of apoptosis, upregulation of p21, and senescence in precursor lymphocytes. This was sufficient to prevent tumorigenesis. However, these mutant mice succumb to severe diabetes and die at an early age. The aim of this study was to determine the pathogenesis of diabetes in these mutant mice. RESEARCH DESIGN AND
methodsWe analyzed the morphology of the pancreatic islets and the function, proliferation rate, and senescence of beta-cells. We also profiled DNA damage and p53 and p21 expression in the pancreas.
resultsNHEJ-p53R172P mutant mice succumb to diabetes at 3-5 months of age. These mice show a progressive decrease in pancreatic islet mass that is independent of apoptosis and innate immunity. We observed an accumulation of DNA damage, accompanied with increased levels of p53 and p21, a significant decrease in beta-cell proliferation, and cellular senescence in the mutant pancreatic islets.
conclusionsCombined DSBs with an absence of p53-dependent apoptosis activate p53-dependent senescence, which leads to a diminished beta-cell self-replication, massive depletion of the pancreatic islets, and severe diabetes. This is a model that connects impaired DNA repair and accumulative DNA damage, a common phenotype in aging individuals, to the onset of diabetes.
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