TITLE

Absence of p53-Dependent Apoptosis Combined With Nonhomologous End-Joining Deficiency Leads to a Severe Diabetic Phenotype in Mice

AUTHOR(S)
Tavana, Omid; Puebla-Osorio, Nahum; Sang, Mei; Chengming Zhu
PUB. DATE
January 2010
SOURCE
Diabetes;Jan2010, Vol. 59 Issue 1, p135
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
OBJECTIVE--Regulation of pancreatic β-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 METHODS--We analyzed the morphology of the pancreatic islets and the function, proliferation rate, and senescence of β-cells. We also profiled DNA damage and p53 and p21 expression in the pancreas. RESULTS--NHEJ-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 β-cell proliferation, and cellular senescence in the mutant pancreatic islets. CONCLUSIONS--Combined DSBs with an absence of p53dependent apoptosis activate p53-dependent senescence, which leads to a diminished β-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. Diabetes 59:135-142, 2010
ACCESSION #
47995259

 

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