title: Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation.
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.
authors.affiliation: Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, andLaboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China;
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department 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;
authors.forename: Yizhou
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, and.
authors.forename: Aiwen
authors.initials: A
authors.lastname: Jin
authors.affiliation: Departments of Biomedical Engineering and.
authors.forename: Andrey P
authors.initials: AP
authors.lastname: Tikunov
authors.affiliation: Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, and.
authors.forename: Lishi
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department 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;
authors.forename: Laura A
authors.initials: LA
authors.lastname: Tollini
authors.affiliation: Department 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;
authors.forename: Patrick
authors.initials: P
authors.lastname: Leslie
authors.affiliation: Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, and.
authors.forename: Tae-Hyung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Nutrition, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Lei O
authors.initials: LO
authors.lastname: Li
authors.affiliation: Nutrition, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Coleman
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and.
authors.forename: Zhennan
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and.
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Chen
authors.affiliation: Departments of Biomedical Engineering and.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Macdonald
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Graves
authors.affiliation: Department 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.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000824:Animal Nutritional Physiological Phenomena / Q000502:physiology*; D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000503:physiopathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015151:Immunoblotting; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015431:Weight Loss / Q000235:genetics / Q000502:physiology
chemical_list: D005227:Fatty Acids; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C016601:afimoxifene; D051736:Proto-Oncogene Proteins c-mdm2; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase