Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis.
Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis.
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Heather L
HL
Armata
Diane
D
Golebiowski
Dae Young
DY
Jung
Hwi Jin
HJ
Ko
Jason K
JK
Kim
Hayla K
HK
Sluss
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009687:Nuclear Proteins; D010544:Peroxidases; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000084622:Sestrins
D000975:Antioxidants; D018797:Cell Cycle Proteins; D005947:Glucose; D006360:Heat-Shock Proteins; D007328:Insulin; D009687:Nuclear Proteins; D010544:Peroxidases; D011506:Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C531059:Sesn1 protein, mouse; D000084622:Sestrins; C549101:Sesn3 protein, mouse; C529380:Sesn2 protein, mouse