The regulation of cellular metabolism by tumor suppressor p53

Abstract

As a hallmark of tumor cells, metabolic alterations play a critical role in tumor development and could be targeted for tumor therapy. Tumor suppressor p53 plays a central role in tumor prevention. As a transcription factor, p53 mainly exerts its function in tumor suppression through its transcriptional regulation of its target genes to initiate various cellular responses. Cell cycle arrest, apoptosis and senescence are most well-understood functions of p53, and are traditionally accepted as the major mechanisms for p53 in tumor suppression. Recent studies have revealed a novel function of p53 in regulation of cellular metabolism. p53 regulates mitochondrial oxidative phosphorylation, glycolysis, glutamine metabolism, lipid metabolism, and antioxidant defense. Through the regulation of these metabolic processes, p53 maintains the homeostasis of cellular metabolism and redox balance in cells, which contributes significantly to the role of p53 as a tumor suppressor. Further understanding of the role and molecular mechanism of p53 in cellular metabolism could lead to the identification of novel targets and development of novel strategies for tumor therapy.

Figure 1

The regulation of cellular metabolism by p53. p53 regulates mitochondrial oxidative phosphorylation, glycolysis, glutaminolysis and fatty acid oxidation in cells. p53 transcriptionally induces SCO2, AIF and p53R2, and physically interacts with mtDNA Poly γ to maintain the mitochondrial integrity and promotes oxidative phosphorylation. p53 reduces glucose uptake through direct repression of the transcription of GLUT 1 & 4, and indirect repression of the expression of GLUT 3. p53 negatively regulates PGM at the protein level and transcriptionally induces TIGAR and Parkin to inhibit glycolysis. Parkin positively regulates PDH, which converts pyruvate into acetyl-CoA. p53 negatively regulates the expression of PDK2, which phosphorylates and inhibits the PDH activity. p53 induces the expression of GLS2, which catalyzes the hydrolysis of glutamine to glutamate. The latter can be further converted into α-KG (α-ketoglutarate). By increasing the levels of α-KG, GLS2 promotes TCA cycle and oxidative phosphorylation. p53 physically interacts with G6PD to negatively regulate the activity of G6PD, and thereby down-regulates PPP (pentose phosphate pathway), a pathway critical for nucleotide synthesis and NADPH production. p53 induces the expression of GAMT and Lipin1 to promote fatty acid oxidation. By producing acetyl-CoA, fatty acid oxidation contributes to the maintenance of TCA cycle and mitochondrial oxidative phosphorylation.

Figure 2

p53 negatively regulates the PI3K/AKT and mTOR pathways to down-regulate glycolysis. The PI3K/AKT and mTOR pathways play critical roles in stimulating glycolysis in tumors. p53 negatively regulates the PI3K/AKT signaling through inducing the expression of IGF-BP3 and PTEN. p53 also negatively regulates mTOR activity through inducing the expression of AMPK-β, Sestrins 1/2, TSC2 and REDD1.

Figure 3

The regulation of oxidative stress and ROS by p53. p53 exerts either antioxidant or prooxidant activity depending on extent of stress signals. Under the conditions of nonstress or low stress, p53 induces antioxidant genes, such as sestrins 1/2, TIGAR, GPX1, ALDH4, GLS2 and Parkin, to lower ROS levels in cells. Furthermore, p53 induces p21 to stabilize NRF2, a transcription factor which induces the expression of antioxidant genes to lower ROS levels. This antioxidant activity protects cells from oxidative stress-induced DNA damage and mutations, and also promotes cell survival. Under the conditions of severe stress, p53 induces prooxidant genes, including PIG3, PIG6, FDRX, Bax and Puma, to further induce ROS levels in cells, which in turn further activates p53. This prooxidant activity leads to the p53-mediated apoptosis and senescence to prevent the propagation of mutation-bearing cells. Thus, both antioxidant and prooxidant activities of p53 contribute to the role of p53 in tumor suppression.