TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

Abstract

The p53 tumor-suppressor protein prevents cancer development through various mechanisms, including the induction of cell-cycle arrest, apoptosis, and the maintenance of genome stability. We have identified a p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator). TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. These functions of TIGAR correlated with an ability to protect cells from ROS-associated apoptosis, and consequently, knockdown of endogenous TIGAR expression sensitized cells to p53-induced death. Expression of TIGAR may therefore modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired. The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage.

Fluorine-18 Fluorodeoxyglucose Uptake in Hepatocellular Carcinoma: Correlation with Glucose Transporters and p53 Expression

“…23,24 Moreover, the loss of the TIGAR (TP53 -induced glycolysis and apoptosis regulator) expression in tumors where p53 is not functional may also explain the high rate of [ 18 F]FDG uptake. 25 Another study suggests that p53 suppression is associated with changes in glucose metabolism detected by PET. 26 Regarding the glucose transporters expression, it appears that there are differences between the cell lines studied.…”

Metabolic reprogramming of the tumor

“…At normal levels, p53 induces TIGAR (Bensaad et al, 2006), which in turn downregulates glycolytic flux through dephosphorylation of fructose-2,6-bisphosphate, an important 6-phosphofructo-1-kinase allosteric activator (Yalcin et al, 2009). On the other hand, p53 fosters mitochondrial respiration through expression of SCO2, a positive regulator of cyclooxygenase, the oxygen-consuming complex of the electron transport chain (ETC) (Matoba et al, 2006), presumably preventing reactive oxygen species (ROS) generation.…”

L’effet Warburg

“…En plus de cette fonction de gène suppresseur de tumeur, p53 participe à la régulation du métabolisme [21,43]. En effet, p53 contrôle négativement la glycolyse en activant l'expression de TIGAR (TP53-induced glycolysis regulator), qui réduit le niveau du fructose-2,6-bisphosphate intracellulaire [22]. De plus, p53 réduit le taux de glucose intracellulaire en inhibant l'expression des transporteurs du glucose GLUT1 et GLUT4 [23].…”