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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis

Heather L Armata1, Diane Golebiowski, Dae Young Jung

  • 1Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Molecular and Cellular Biology
|October 20, 2010
PubMed

Insights

Ataxia telangiectasia (A-T) is linked to metabolic issues. P53 phosphorylation by ATM is crucial for regulating glucose homeostasis and preventing insulin resistance.

Area of Science:

  • Biochemistry
  • Genetics
  • Metabolic Disease

Background:

  • Ataxia telangiectasia (A-T) is a genetic disorder causing neurodegeneration, cancer predisposition, and metabolic dysfunction.
  • ATM protein kinase, mutated in A-T, plays a role in metabolic diseases characterized by insulin resistance and dyslipidemia.
  • ATM regulates p53 tumor suppressor activity via phosphorylation at Ser15, a site critical for its transcriptional function.

Purpose of the Study:

  • To investigate if the ATM pathway regulating insulin resistance involves p53 phosphorylation.
  • To determine the role of p53 phosphorylation at Ser15 in glucose homeostasis and insulin sensitivity.

Main Methods:

  • Examined insulin sensitivity in mice with a germline mutation replacing the p53 phosphorylation site (Ser18 in mice, Ser15 in humans) with alanine.
  • Assessed glucose homeostasis, insulin resistance, and insulin signaling pathways.
  • Utilized N-Acetyl cysteine (NAC) treatment and dietary antioxidant supplementation.

Main Results:

  • Mice lacking p53 phosphorylation at Ser18 exhibited severe glucose homeostasis defects, including glucose intolerance and insulin resistance.
  • Insulin resistance correlated with reduced antioxidant gene expression and impaired insulin signaling.
  • NAC treatment restored insulin signaling in fibroblasts, and dietary antioxidants improved glucose tolerance in deficient mice.

Conclusions:

  • p53 phosphorylation on an ATM site is a key mechanism in the physiological regulation of glucose homeostasis.
  • This pathway is critical for maintaining metabolic health and preventing insulin resistance.
  • Targeting this pathway may offer therapeutic strategies for metabolic disorders.

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