title: p53 attenuates AKT signaling by modulating membrane phospholipid composition.
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.
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rueda-Rincon
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bloch
authors.affiliation: KU Leuven - University of Leuven, Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Leuven, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: Derua
authors.affiliation: KU Leuven - University of Leuven, Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, VIB, Leuven, Belgium.|KU Leuven - University of Leuven, Department of Human Genetics, Laboratory for Molecular Cancer Biology, VIB, Leuven, Belgium.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Vyas
authors.affiliation: Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands.|Netherlands Metabolomics Centre, Leiden, The Netherlands.
authors.forename: Amy
authors.initials: A
authors.lastname: Harms
authors.affiliation: Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands.|Netherlands Metabolomics Centre, Leiden, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hankemeier
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium.
authors.forename: Niamat Ali
authors.initials: NA
authors.lastname: Khan
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Dehairs
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium.
authors.forename: Muralidhararao
authors.initials: M
authors.lastname: Bagadi
authors.affiliation: Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Gynécologie, Bruxelles, Belgium.
authors.forename: Maria Mercedes
authors.initials: MM
authors.lastname: Binda
authors.affiliation: KU Leuven - University of Leuven, Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Leuven, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.affiliation: KU Leuven - University of Leuven, Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, VIB, Leuven, Belgium.|KU Leuven - University of Leuven, Department of Human Genetics, Laboratory for Molecular Cancer Biology, VIB, Leuven, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.affiliation: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium.
authors.forename: Johannes V
authors.initials: JV
authors.lastname: Swinnen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018450:Disease Progression; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism*; D010743:Phospholipids / Q000737:chemistry*; D010879:Piperazines / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005231:Fatty Acids, Unsaturated; D007093:Imidazoles; D008055:Lipids; D010743:Phospholipids; D010879:Piperazines; D051780:Sterol Regulatory Element Binding Protein 1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D013230:Stearoyl-CoA Desaturase; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: SCD; SREBP; cancer; p53; phospholipids