title: p53 promotes the expression of gluconeogenesis-related genes and enhances hepatic glucose production.
abstract: BACKGROUND
  The p53 tumor suppressor protein is a transcription factor that initiates transcriptional programs aimed at inhibiting carcinogenesis. p53 represses metabolic pathways that support tumor development (such as glycolysis and the pentose phosphate pathway (PPP)) and enhances metabolic pathways that are considered counter-tumorigenic such as fatty acid oxidation.
  
  
  RESULTS
  In an attempt to comprehensively define metabolic pathways regulated by p53, we performed two consecutive high-throughput analyses in human liver-derived cells with varying p53 statuses. A gene expression microarray screen followed by constraint-based modeling (CBM) predicting metabolic changes imposed by the transcriptomic changes suggested a role for p53 in enhancing gluconeogenesis (de novo synthesis of glucose). Examining glucogenic gene expression revealed a p53-dependent induction of genes involved in both gluconeogenesis (G6PC, PCK2) and in supplying glucogenic precursors (glycerol kinase (GK), aquaporin 3 (AQP3), aquaporin 9 (AQP9) and glutamic-oxaloacetic transaminase 1 (GOT1)). Accordingly, p53 augmented hepatic glucose production (HGP) in both human liver cells and primary mouse hepatocytes.
  
  
  CONCLUSIONS
  These findings portray p53 as a novel regulator of glucose production. By facilitating glucose export, p53 may prevent it from being shunted to pro-cancerous pathways such as glycolysis and the PPP. Thus, our findings suggest a metabolic pathway through which p53 may inhibit tumorigenesis.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot, 76100, Israel. goldstein.ido@gmail.com.
authors.forename: Ido
authors.initials: I
authors.lastname: Goldstein
authors.forename: Keren
authors.initials: K
authors.lastname: Yizhak
authors.forename: Shalom
authors.initials: S
authors.lastname: Madar
authors.forename: Naomi
authors.initials: N
authors.lastname: Goldfinger
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
authors.forename: Varda
authors.initials: V
authors.lastname: Rotter