p53 attenuates AKT signaling by modulating membrane phospholipid composition

// Natalia Rueda-Rincon 1 , Katarzyna Bloch 1 , Rita Derua 2 , Rajesh Vyas 3, 4 , Amy Harms 5, 6 , Thomas Hankemeier 5, 6 , Niamat Ali Khan 1 , Jonas Dehairs 1 , Muralidhararao Bagadi 1 , Maria Mercedes Binda 7 , Etienne Waelkens 2 , Jean-Christophe Marine 3, 4 , Johannes V. Swinnen 1 1 KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium 2 KU Leuven - University of Leuven, Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Leuven, Belgium 3 KU Leuven - University of Leuven, Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, VIB, Leuven, Belgium 4 KU Leuven - University of Leuven, Department of Human Genetics, Laboratory for Molecular Cancer Biology, VIB, Leuven, Belgium 5 Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands 6 Netherlands Metabolomics Centre, Leiden, The Netherlands 7 Institut de Recherche Experimentale et Clinique (IREC), Pole de Gynecologie, Bruxelles, Belgium Correspondence to: Johannes V. Swinnen, e-mail: johan.swinnen@med.kuleuven.be Keywords: p53, SCD, SREBP, phospholipids, cancer Received: February 03, 2015      Accepted: May 21, 2015      Published: June 03, 2015 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.