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p53 promotes the expression of gluconeogenesis-related genes and enhances hepatic glucose production

Ido Goldstein1*, Keren Yizhak2, Shalom Madar1, Naomi Goldfinger1, Eytan Ruppin23 and Varda Rotter1

Author Affiliations

1 Department of Molecular Cell Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot, 76100, Israel

2 Blavatnik School of Computer Science, Tel Aviv University, Haim Levanon, Tel Aviv, 69978, Israel

3 Sackler School of Medicine, Tel Aviv University, Haim Levanon, Tel Aviv, 69978, Israel

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Cancer & Metabolism 2013, 1:9  doi:10.1186/2049-3002-1-9

Published: 4 February 2013



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.


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.


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.

p53; Gluconeogenesis; Hepatic glucose production; Diabetes