ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress

Mol Cell. 2011 Nov 4;44(3):491-501. doi: 10.1016/j.molcel.2011.08.038.

Abstract

The p53 protein is activated by stress signals and exhibits both protective and death-promoting functions that are considered important for its tumor suppressor function. Emerging evidence points toward an additional role for p53 in metabolism. Here, we identify Lpin1 as a p53-responsive gene that is induced in response to DNA damage and glucose deprivation. Lpin1 is essential for adipocyte development and fat metabolism, and mutation in this gene is responsible for the lypodystrophy phenotype in fld mice. We show that p53 and Lpin1 regulate fatty acid oxidation in mouse C2C12 myoblasts. p53 phosphorylation on Ser18 in response to low glucose is ROS and ATM dependent. Lpin1 expression in response to nutritional stress is controlled through the ROS-ATM-p53 pathway and is conserved in human cells. Lpin1 provides a critical link between p53 and metabolism that may be an important component in mediating the tumor suppressor function of p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • DNA Damage
  • DNA-Binding Proteins / metabolism
  • Energy Metabolism*
  • Enzyme Activation
  • Fatty Acids / metabolism*
  • Glucose / deficiency*
  • Humans
  • Mice
  • Mice, Knockout
  • Myoblasts / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nutritional Status*
  • Oxidation-Reduction
  • Oxidative Stress*
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism*
  • Serine
  • Time Factors
  • Transfection
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Fatty Acids
  • Nuclear Proteins
  • Reactive Oxygen Species
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Serine
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • LPIN1 protein, human
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase
  • Glucose