Abstract A47: The regulation of TIGAR

Abstract

Abstract The p53 tumor suppressor protein inhibits the development of cancer by initiating various cellular responses including apoptosis, senescence and cell cycle arrest. In addition to this, recent studies have found that p53 is also able to influence cell metabolism. TP53-induced glycolysis and apoptosis regulator (TIGAR) was discovered as a p53 target functioning as a fructose-2,6-bisphosphatase. In this way, TIGAR can modulate glucose metabolism, resulting in enhanced NADPH production and antioxidant defence. While discovered as a p53 target, basal expression of TIGAR is not affected by loss of p53 or its family member TAp73 in mice and increased expression of TIGAR in the small intestines is still observed following irradiation in these animals. Moreover, this induction is retained in mice deleted of both p53 and TAp73, demonstrating that TIGAR expression is not dependent on either of these transcription factors. In mouse intestines, TIGAR is important in repair following tissue injury and mice that are TIGAR-deficient show elevated levels of oxidative stress following damage. As the Wnt/Myc signalling pathway is important in cellular proliferation and tissue regeneration, its potential role in regulating TIGAR was investigated. Deletion of APC in mouse intestines, leading to high Wnt pathway activation, results in an increased expression of TIGAR, suggesting that the Wnt/Myc signalling pathway may influence the regulation of TIGAR. Together, the results suggest that TIGAR can be regulated through p53-dependent and independent mechanisms to contribute to the control of tissue regeneration and tumorigenesis. Funded by Cancer Research UK, PL is a recipient of an MRC studentship. Citation Format: Pearl Lee, Eric C. Cheung, Karen H. Vousden. The regulation of TIGAR. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A47.