p53 attenuates AKT signaling by modulating membrane phospholipid composition

Oncotarget. 2015 Aug 28;6(25):21240-54. doi: 10.18632/oncotarget.4067.

Abstract

The p53 tumor suppressor is the central component of a complex network of signaling pathways that protect organisms against the propagation of cells carrying oncogenic mutations. Here we report a previously unrecognized role of p53 in membrane phospholipids composition. By repressing the expression of stearoyl-CoA desaturase 1, SCD, the enzyme that converts saturated to mono-unsaturated fatty acids, p53 causes a shift in the content of phospholipids with mono-unsaturated acyl chains towards more saturated phospholipid species, particularly of the phosphatidylinositol headgroup class. This shift affects levels of phosphatidylinositol phosphates, attenuates the oncogenic AKT pathway, and contributes to the p53-mediated control of cell survival. These findings expand the p53 network to phospholipid metabolism and uncover a new molecular pathway connecting p53 to AKT signaling.

Keywords: SCD; SREBP; cancer; p53; phospholipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Disease Progression
  • Fatty Acids, Unsaturated / chemistry
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Imidazoles / metabolism
  • Lipids / chemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / metabolism*
  • Phospholipids / chemistry*
  • Piperazines / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Signal Transduction
  • Stearoyl-CoA Desaturase / metabolism*
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Fatty Acids, Unsaturated
  • Imidazoles
  • Lipids
  • Phospholipids
  • Piperazines
  • Sterol Regulatory Element Binding Protein 1
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • nutlin 3
  • Stearoyl-CoA Desaturase
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt