title: MDM4 actively restrains cytoplasmic mTORC1 by sensing nutrient availability.
abstract: Many tumor-related factors have shown the ability to affect metabolic pathways by paving the way for cancer-specific metabolic features. Here, we investigate the regulation of mTORC1 by MDM4, a p53-inhibitor with oncogenic or anti-survival activities depending on cell growth conditions.
  
  
  
  MDM4-mTOR relationship was analysed through experiments of overexpression or silencing of endogenous proteins in cell culture and using purified proteins in vitro. Data were further confirmed in vivo using a transgenic mouse model overexpressing MDM4. Additionally, the Cancer Genome Atlas (TCGA) database (N = 356) was adopted to analyze the correlation between MDM4 and mTOR levels and 3D cultures were used to analyse the p53-independent activity of MDM4.
  
  
  
  Following nutrient deprivation, MDM4 impairs mTORC1 activity by binding and inhibiting the kinase mTOR, and contributing to maintain the cytosolic inactive pool of mTORC1. This function is independent of p53. Inhibition of mTORC1 by MDM4 results in reduced phosphorylation of the mTOR downstream target p70S6K1 both in vitro and in vivo in a MDM4-transgenic mouse. Consistently, MDM4 reduces cell size and proliferation, two features controlled by p70S6K1, and, importantly, inhibits mTORC1-mediated mammosphere formation. Noteworthy, MDM4 transcript levels are significantly reduced in breast tumors characterized by high mTOR levels.
  
  
  
  Overall, these data identify MDM4 as a nutrient-sensor able to inhibit mTORC1 and highlight its metabolism-related tumor-suppressing function.
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00143, Rome, Italy. chicca.mancini@tiscali.it.|PostGraduate School of Endocrinology and Metabolic Diseases, Institute of Pathology, Catholic University of Rome, 00168, Rome, Italy. chicca.mancini@tiscali.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00143, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Teveroni
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, 3000, Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000, Leuven, Belgium.
authors.forename: Giusy
authors.initials: G
authors.lastname: Di Conza
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00143, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Monteleone
authors.affiliation: European Brain Research Institute (EBRI) Rita Levi-Montalcini, 00143, Rome, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Arisi
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00143, Rome, Italy.
authors.forename: Marsha
authors.initials: M
authors.lastname: Pellegrino
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00143, Rome, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Buttarelli
authors.affiliation: Proteomic and Metabonomic Laboratory, Fondazione Santa Lucia, 00143, Rome, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Pieroni
authors.affiliation: European Brain Research Institute (EBRI) Rita Levi-Montalcini, 00143, Rome, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: D'Onofrio
authors.affiliation: Proteomic and Metabonomic Laboratory, Fondazione Santa Lucia, 00143, Rome, Italy.|Institute of Biochemistry and Biochemical Clinic, Catholic University of Rome, 00168, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.affiliation: PostGraduate School of Endocrinology and Metabolic Diseases, Institute of Pathology, Catholic University of Rome, 00168, Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pontecorvi
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, 3000, Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00143, Rome, Italy. fabiola.moretti@cnr.it.
authors.forename: Fabiola
authors.identifier: 0000-0002-2691-1254
authors.initials: F
authors.lastname: Moretti
mesh_terms: D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Aminoacid; MDM4; Nutrient deprivation; mTOR; p53