Requirement of the ATM/p53 Tumor Suppressor Pathway for Glucose Homeostasis

Abstract

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.

We thank Roger Davis for critical reading of the manuscript; Guadalupe Sabio, Anja Jaeschke, and other members of the Davis laboratory for helpful discussions and invaluable technical assistance; David Garlick for histology analysis; Ceren Acer, Chrisitine Delaney, and Charissa Cottonham for assistance with real-time PCR analysis; Punita Shroff for help with hydrogen peroxide experiments; and Andrei Budanov for kindly providing plasmids.

These studies were supported by a Pilot & Feasibility grant from the UMass Diabetes Endocrinology Research Center (NIH P30 DK32520 to H.K.S.), Worcester Foundation for Biomedical Research (to H.S.K.), and by grants from the NIH (DK80756 to J.K.K.) and the American Diabetes Association (7-07-RA-80 to J.K.K.). Core resources supported by the Diabetes Endocrinology Research Center grant (DK32520) were also used. Hayla K. Sluss and Jason K. Kim are members of the UMass DERC (DK32520). Part of this study was performed at the Penn State Diabetes & Obesity Mouse Phenotyping Center (supported by the Pennsylvania Department of Health and Tobacco Settlement Funds).

We declare that we have no conflicts of interest.