The regulation of TIGAR

QH301 Biology;RC0254 Neoplasms. Tumors. Oncology (including Cancer)

Lee, Pearl ; Vousden, Karen H.

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: TIGAR, cancer, metabolism, ROS;   

Others  :  http://theses.gla.ac.uk/7026/7/2015leephd.pdf

来源: University of Glasgow

【 摘 要 】

TIGAR (TP53-induced glycolysis and apoptosis regulator) functions to promote antioxidant defence, with a loss of TIGAR associated with a defect in a cell’s ability to control reactive oxygen species (ROS) and resultant oxidative damage. TIGAR can function as a fructose-2,6-bisphosphatase, lowering the levels of fructose-2,6- bisphosphate, which is an activator of phosphofructokinase-1. As a consequence, TIGAR activity results in a dampening of the glycolytic pathway and, by enhancing the pentose phosphate pathway, increases cellular antioxidant capacity by promoting the generation of NADPH and GSH.Although TIGAR is clearly a transcriptional target of the tumour suppressor p53 in human cells, the activation of TIGAR expression in mouse cells in vitro and in a mouse model of intestinal regeneration was not dependent on p53 or its family member TAp73. However, TIGAR expression was strongly induced in the mouse intestine during proliferation following damage or APC loss, suggesting a role for the Wnt signalling pathway. The increase in TIGAR expression seen in response to APC loss was lost after simultaneous deletion of c-Myc, suggesting that TIGAR responds to c-Myc activation downstream of the Wnt signalling pathway. While TIGAR may be a direct Myc target, Myc was shown to induce ROS, which were also found to regulate the expression of TIGAR.In order to further understand the function of TIGAR, a TIGAR-deficient mouse was generated and TIGAR was found to play a role in supporting intestinal regeneration by lowering oxidative stress in the small intestinal crypts following tissue damage by irradiation or cisplatin treatment. Moreover, TIGAR-null mice showed decreased tumour development in a model of intestinal adenoma. In particular, it was found that TIGAR acts to lower the damaging pool of ROS during oxidative stress. Through this, TIGAR can function to promote tumourigenesis and elevated TIGAR expression has been observed in various cancer types, independently of p53 status. This suggests that a deregulated expression of TIGAR may play a role in supporting rather than inhibiting cancer development.This study reveals p53-independent mechanisms by which TIGAR is regulated and how TIGAR can contribute to promote cell growth and tumourigenesis.