Article (Scientific journals)
Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53.
Riscal, Romain; Schrepfer, Emilie; Arena, Giuseppe et al.
2016In Molecular Cell, 62 (6), p. 890-902
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Keywords :
Activating Transcription Factor 4/genetics/metabolism; Animals; Carcinoma, Non-Small-Cell Lung/genetics/metabolism/pathology; Carrier Proteins/genetics/metabolism; Cell Proliferation; Chromatin/genetics/metabolism; Chromatin Assembly and Disassembly; Colonic Neoplasms/genetics/metabolism/pathology; Gene Expression Regulation, Neoplastic; Glycine/metabolism; HCT116 Cells; Homeostasis; Humans; Lung Neoplasms/genetics/metabolism/pathology; Membrane Proteins/genetics/metabolism; Mice, Nude; Mutation; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-mdm2/genetics/metabolism; RNA Interference; Serine/metabolism; Thyroid Hormones/genetics/metabolism; Time Factors; Transcription, Genetic; Transfection; Tumor Burden; Tumor Suppressor Protein p53/genetics/metabolism
Abstract :
[en] The mouse double minute 2 (MDM2) oncoprotein is recognized as a major negative regulator of the p53 tumor suppressor, but growing evidence indicates that its oncogenic activities extend beyond p53. Here, we show that MDM2 is recruited to chromatin independently of p53 to regulate a transcriptional program implicated in amino acid metabolism and redox homeostasis. Identification of MDM2 target genes at the whole-genome level highlights an important role for ATF3/4 transcription factors in tethering MDM2 to chromatin. MDM2 recruitment to chromatin is a tightly regulated process that occurs during oxidative stress and serine/glycine deprivation and is modulated by the pyruvate kinase M2 (PKM2) metabolic enzyme. Depletion of endogenous MDM2 in p53-deficient cells impairs serine/glycine metabolism, the NAD(+)/NADH ratio, and glutathione (GSH) recycling, impacting their redox state and tumorigenic potential. Collectively, our data illustrate a previously unsuspected function of chromatin-bound MDM2 in cancer cell metabolism.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Riscal, Romain
Schrepfer, Emilie
Arena, Giuseppe  ;  IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier F-34298, France
Cissé, Madi Y.
Bellvert, Floriant
Heuillet, Maud
Rambow, Florian
Bonneil, Eric
Sabourdy, Frédérique
Vincent, Charles
Ait-Arsa, Imade
Levade, Thierry
Thibaut, Pierre
Marine, Jean-Christophe
Portais, Jean-Charles
Sarry, Jean-Emmanuel
Le Cam, Laurent
Linares, Laetitia K.
More authors (8 more) Less
External co-authors :
yes
Language :
English
Title :
Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53.
Publication date :
2016
Journal title :
Molecular Cell
ISSN :
1097-4164
Publisher :
Cell Press, United States - Massachusetts
Volume :
62
Issue :
6
Pages :
890-902
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright © 2016 Elsevier Inc. All rights reserved.
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