Format

Send to:

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):E2414-22. doi: 10.1073/pnas.1315605111. Epub 2014 May 28.

Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation.

Author information

  • 1Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, andLaboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China;
  • 2Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, andCurriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
  • 3Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, and.
  • 4Departments of Biomedical Engineering and.
  • 5Nutrition, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
  • 6Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and.
  • 7Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
  • 8Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, andLaboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China;Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 ypzhang@med.unc.edu.

Abstract

The tumor suppressor p53 has recently been shown to regulate energy metabolism through multiple mechanisms. However, the in vivo signaling pathways related to p53-mediated metabolic regulation remain largely uncharacterized. By using mice bearing a single amino acid substitution at cysteine residue 305 of mouse double minute 2 (Mdm2(C305F)), which renders Mdm2 deficient in binding ribosomal proteins (RPs) RPL11 and RPL5, we show that the RP-Mdm2-p53 signaling pathway is critical for sensing nutrient deprivation and maintaining liver lipid homeostasis. Although the Mdm2(C305F) mutation does not significantly affect growth and development in mice, this mutation promotes fat accumulation under normal feeding conditions and hepatosteatosis under acute fasting conditions. We show that nutrient deprivation inhibits rRNA biosynthesis, increases RP-Mdm2 interaction, and induces p53-mediated transactivation of malonyl-CoA decarboxylase (MCD), which catalyzes the degradation of malonyl-CoA to acetyl-CoA, thus modulating lipid partitioning. Fasted Mdm2(C305F) mice demonstrate attenuated MCD induction and enhanced malonyl-CoA accumulation in addition to decreased oxidative respiration and increased fatty acid accumulation in the liver. Thus, the RP-Mdm2-p53 pathway appears to function as an endogenous sensor responsible for stimulating fatty acid oxidation in response to nutrient depletion.

PMID:
24872453
[PubMed - indexed for MEDLINE]
PMCID:
PMC4060669
Free PMC Article

Publication Types, MeSH Terms, Substances, Grant Support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk