Debra Franck1,2, Laura Tracy1,2, Heather L Armata1, Christine L Delaney1, Dae Young Jung3, Hwi Jin Ko3, Helena Ong3, Jason K Kim1,3, Heidi Scrable4, Hayla K Sluss1. 1. a Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School , Worcester, MA, USA. 2. b Department of Biology, Worcester Polytechnic Institute , Worcester, MA, USA. 3. c Program in Molecular Medicine, University of Massachusetts Medical School , Worcester, MA, USA. 4. d Mayo Clinic, University of Massachusetts Medical School , Worcester, MA, USA.
Abstract
AIM: To test the transactivation domain-mediated control of glucose homeostasis by the tumor suppressor p53. BACKGROUND: The tumor suppressor p53 has a critical role in maintenance of glucose homeostasis. Phosphorylation of Ser18 in the transaction domain of p53 controls the expression of Zpf385a, a zinc finger protein that regulates adipogenesis and adipose function. This results suggest that the transactivation domain of p53 is essential to the control of glucose homeostasis. MATERIALS AND METHODS: Mice with mutations in the p53 transactivation domain were examined for glucose homeostasis as well as various metabolic parameters. Glucose tolerance and insulin tolerance tests were performed on age matched wild type and mutant animals. In addition, mice expressing increased dosage of p53 were also examined. RESULTS: Mice with a mutation in p53Ser18 exhibit reduced Zpf385a expression in adipose tissue, adipose tissue-specific insulin resistance, and glucose intolerance. Mice with relative deficits in the transactivation domain of p53 exhibit similar defects in glucose homeostasis, while "Super p53" mice with an increased dosage of p53 exhibit improved glucose tolerance. CONCLUSION: These data support the role of an ATM-p53 cellular stress axis that helps combat glucose intolerance and insulin resistance and regulates glucose homeostasis.
AIM: To test the transactivation domain-mediated control of glucose homeostasis by the tumor suppressor p53. BACKGROUND: The tumor suppressor p53 has a critical role in maintenance of glucose homeostasis. Phosphorylation of Ser18 in the transaction domain of p53 controls the expression of Zpf385a, a zinc finger protein that regulates adipogenesis and adipose function. This results suggest that the transactivation domain of p53 is essential to the control of glucose homeostasis. MATERIALS AND METHODS:Mice with mutations in the p53 transactivation domain were examined for glucose homeostasis as well as various metabolic parameters. Glucose tolerance and insulin tolerance tests were performed on age matched wild type and mutant animals. In addition, mice expressing increased dosage of p53 were also examined. RESULTS:Mice with a mutation in p53Ser18 exhibit reduced Zpf385a expression in adipose tissue, adipose tissue-specific insulin resistance, and glucose intolerance. Mice with relative deficits in the transactivation domain of p53 exhibit similar defects in glucose homeostasis, while "Super p53" mice with an increased dosage of p53 exhibit improved glucose tolerance. CONCLUSION: These data support the role of an ATM-p53 cellular stress axis that helps combat glucose intolerance and insulin resistance and regulates glucose homeostasis.
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