The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein

Abstract

In response to stress, p53 initiates the transcriptional regulation of selected target genes and various cellular responses, including cell cycle arrest, apoptosis and senescence. Recent studies revealed two additional functions of p53 in the regulation of IGF-1/AKT/mTOR pathways and energy metabolism, contributing to p53's role as a tumor suppressor. Oncogenic processes give rise to metabolic pathways focused upon the use of aerobic glycolysis (the Warburg effect) and the pentose shunt, providing higher levels of reducing activities. p53 shuts down these pathways and refocuses cells to utilize mitochondrial oxidative phosphorylation, thereby maximizing efficient ATP production and minimizing the synthesis of substrates for cell division. The use of these alternative metabolic pathways is an integral part of both normal and oncogenic phenotypes.

Figure 1. p53 and its signaling pathway

Various kinds of stress signals are detected by cells and communicated to the p53 protein and its core constituents by the mediators. Stress signals result in the degradation of the MDM2 protein and the increase in the levels and activity of the p53 protein. Once activated, p53 selectively transcribes a group of its target genes (shown are representative genes) and initiates cellular responses to exert various functions.

Figure 2. The coordinated regulation of p53, mTOR and IGF-1/AKT pathways

p53 inhibits IGF-1/AKT and mTOR pathways thorough its induction of IGF-BP3, PTEN, TSC2, AMPK β1, Sestrin1/2 and REDD1 in response to stress. mTORC1 activates the α-4 subunit of the PP2A phosphatase to dephosphorylate p53 on Ser15 to inactivate p53, while AMPK phosphorylates p53 on Ser15 to activate p53. AKT-MDM2-p53 forms a negative feedback loop to negatively regulate p53, while p53-PTEN-AKT-MDM2 forms a positive loop to positively regulate p53. Furthermore, p53 activates autophagy through its regulation of mTOR pathway and p53 target genes, including DRAM, PUMA and Bax. These extensive communication and coordination between p53 and IGF-1/AKT/mTOR pathways slows down cell growth and division to prevent the accumulations of errors in response to stress and restores cellular homeostasis after stress is resolved.

Figure 3. p53 regulation of energy metabolism

p53 induces the expression of TIGAR and inhibits the expression of PGM to inhibit glycolysis. p53 induces SCO2 and GLS2 to enhance mitochondrial respiration, and induces p53R2 to maintain mitochondrial DNA. Furthermore, p53 represses the transcriptional expression of GLUT1 and GLUT4, and inhibits the NF-κB pathway to reduce the expression of GLUT3 to reduce glycolysis. Thus, p53 inhibits glycolysis and enhances mitochondrial respiration in cells.