Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53.
Mol Cell
; 62(6): 890-902, 2016 06 16.
Article
in En
| MEDLINE
| ID: mdl-27264869
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Serine
/
Chromatin
/
Tumor Suppressor Protein p53
/
Colonic Neoplasms
/
Carcinoma, Non-Small-Cell Lung
/
Chromatin Assembly and Disassembly
/
Proto-Oncogene Proteins c-mdm2
/
Lung Neoplasms
Type of study:
Prognostic_studies
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2016
Document type:
Article
Affiliation country: