Glucose Tolerance in Mice is Linked to the Dose of the p53 Transactivation Domain

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.

• p53
• Glucose intolerance
• Mouse genetics

ACKNOWLEDGMENTS

We thank Roger Davis for critical reading of the manuscript, Judy O’Reilly for invaluable technical assistance, David Garlick for histology analysis, and Ceren Acer and Charissa Cottonham for assistance with real-time PCR analysis. We thank Dr. Serrano for the p53^super mice. CD was supported by a Fuller Fellowship from the American Cancer Society. These studies were supported by a Pilot & Feasibility grant from the UMASS Diabetes Endocrinology Research Center (NIH P30 DK32520) (to HKS), a Worcester Foundation Annual Research Award from the Worcester Foundation for Biomedical Research (to HKS) and by grants from the NIH (DK80756 to JKK and AG26094 to HS), the American Diabetes Association (7-07-RA-80 to JKK), and the Ellison Medical Research Foundation (to HS). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Core resources, including the UMASS Mouse Metabolic Phenotyping Center, 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).

Declaration of Interest

The authors declare they have no conflict of interest. The authors alone are responsible for the content and writing of this article.