MDM2 regulates genes involved in serine metabolism and redox homeostasis in a p53-independent manner.
Major finding: MDM2 regulates genes involved in serine metabolism and redox homeostasis in a p53-independent manner.
Mechanism: Serine/glycine deprivation recruits MDM2 to chromatin for ATF-dependent target gene transcription.
Impact: MDM2 may be a therapeutic target to disrupt tumor metabolism.
MDM2 is an oncogenic E3 ubiquitin ligase that is overexpressed in many tumors and negatively regulates p53. Recent evidence indicates that MDM2 also has p53-independent oncogenic functions, but these have not been well characterized. Riscal and colleagues assessed the localization of MDM2 in a panel of cancer cell lines and found that MDM2 was localized to the cyto- and nucleosoluble fractions consistent with its E3 ligase activity. However, a substantial amount of MDM2 was also detected in the chromatin-enriched fraction and was not altered by p53 knockdown, indicating p53-independent recruitment to chromatin. Chromatin immunoprecipitation sequencing and microarray analysis identified 159 genes that were upregulated by MDM2 binding. MDM2 bound loci were enriched for activating transcription factor (ATF) 3 and 4 binding motifs, and ATF3/4 was found to recruit MDM2 to target gene promoters. MDM2 target genes were enriched for those involved in serine, glycine, glutamine, and cysteine metabolism, and serine or glycine deprivation increased MDM2 chromatin binding at target genes to sustain serine/glycine biosynthesis and promote tumor growth. MDM2 targets also included genes involved in redox homeostasis, and MDM2 depletion resulted in reduced glutathione oxidation, a decreased NAD+/NADH ratio, and increased reactive oxygen species (ROS) levels. MDM2 recruitment to its target genes was regulated by pyruvate kinase isoform M2 (PKM2), an enzyme that is inhibited by ROS and allosterically activated by serine. The PKM2 complex phosphorylated MDM2, reducing its recruitment to chromatin. Together, these findings establish a p53-independent mechanism by which MDM2 promotes tumor growth via regulation of amino acid metabolism and redox homeostasis, which may have therapeutic implications for tumors in which MDM2 is overexpressed.
Riscal R, Schrepfer E, Arena G, Cissé MY, Bellvert F, Heuillet M, et al. Chromatin-bound MDM2 regulates serine metabolism and redox homeostasis independently of p53. Mol Cell 2016 June 2 [Epub ahead of print].
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