Emerging Roles of p53 Family Members in Glucose Metabolism

Abstract

Glucose is the key source for most organisms to provide energy, as well as the key source for metabolites to generate building blocks in cells. The deregulation of glucose homeostasis occurs in various diseases, including the enhanced aerobic glycolysis that is observed in cancers, and insulin resistance in diabetes. Although p53 is thought to suppress tumorigenesis primarily by inducing cell cycle arrest, apoptosis, and senescence in response to stress, the non-canonical functions of p53 in cellular energy homeostasis and metabolism are also emerging as critical factors for tumor suppression. Increasing evidence suggests that p53 plays a significant role in regulating glucose homeostasis. Furthermore, the p53 family members p63 and p73, as well as gain-of-function p53 mutants, are also involved in glucose metabolism. Indeed, how this protein family regulates cellular energy levels is complicated and difficult to disentangle. This review discusses the roles of the p53 family in multiple metabolic processes, such as glycolysis, gluconeogenesis, aerobic respiration, and autophagy. We also discuss how the dysregulation of the p53 family in these processes leads to diseases such as cancer and diabetes. Elucidating the complexities of the p53 family members in glucose homeostasis will improve our understanding of these diseases.

Keywords: autophagy; cancer; diabetes; glucose metabolism; glycolysis; mitochondria; p53; p53 mutant; p63; p73.

Figure 1

Regulation of glycolysis and gluconeogenesis by p53 family members and mutant p53. p53 inhibits glycolysis either by activating or repressing the transcriptions of genes or microRNAs involved in glycolysis, or by modulating the activity of the molecules involved in glycolysis in a transcription-independent manner. On the other hand, p53 promotes gluconeogenesis in a transcription-dependent manner. The mutant p53 and p53 family members p63 and p73 are also involved in the regulation of glycolysis. The positive regulations are shown in blue arrows, and the negative regulations are shown in red T-bar lines. The arrows in black indicate the conversion or the movement of molecules. C: carbon, P: phosphate, PPP: pentose phosphate pathway, G6P: glucose 6-phosphate, F6P: fructose 6-phosphate, F1,6P₂: fructose 2,6-bisphosphate, G3P: glyceraldehyde 3-phosphate, 1,3-BPG: 1,3-bisphosphoglyceric acid, 3PG: 3-phosphoglycerate, 2PG: 2-phosphoglycerate, 6PG: 6-phosphogluconate, F2,6P₂: fructose 2,6-bisphosphate, PEP: phosphoenolpyruvate, DHAP: dihydroxyacetone phosphate, TCA: tricarboxylic acid, GLUT: glucose transporter, IAPP: islet amyloid polypeptide, NFκB; nuclear factor kappa B, RRAD; Ras-related glycolysis inhibitor and calcium channel regulator, HK2: hexokinase 2, PAK4: p21-activated kinase 4, PFKFB: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, G6PD: gucose-6-phosphate dehydrogenase, TIGAR: TP53-induced glycolysis and apoptosis regulator, PFK1: phosphofructokinase-1, PGM: phosphoglycerate mutase, MCT1: monocarboxylic acid transporter 1, PANK1: pantothenate kinases-1, CHREBP: carbohydrate responsive element binding protein, p53mt: p53 mutant, TAp63 and TAp73: full-length isoforms of p63 and p73, ΔNp63: the N-terminus deleted isoform of p63.

Figure 2

Regulation of mitochondrial metabolism by p53 family members. p53 enhances mitochondrial functions by inducing or repressing genes, or by interacting with proteins, both of which are involved in oxidative phosphorylation, the TCA cycle, and mitochondrial DNA (mtDNA) homeostasis. p63 and p73 are also involved in some of the steps in mitochondrial functions. The positive regulations are shown in blue arrows, and the negative regulations are shown in red T-bar lines. ME: malic enzyme, PDC: pyruvate dehydrogenase complex, PDK2: pyruvate dehydrogenase complex 2, TP53 inducible subunit M2B, TFAM: mitochondrial transcription factor A, mtSSB: mitochondrial single-strand binding protein, GLS2: glutaminase 2, AIF: apoptosis-inducing factor, SCO2: cytochrome c oxidase assembly protein, FDXR: ferredoxin reductase, PGC: peroxisome proliferator-activated receptor gamma coactivator, MIEAP: mitochondria-eating protein.

Figure 3

Regulation of autophagy by p53 family members and mutant p53. The regulation of autophagy by p53 is complex. p53 enhances autophagy by inducing distinct target genes, whereas cytoplasmic p53 inhibits autophagy. Alternative reading frame protein (ARF), an upstream regulator of p53, also enhances autophagy. A core autophagy regulator, ATG7, induces p21 via activating p53 through ATG7-p53 binding, contributing to cell survival during nutrient deprivation. p73 also induces multiple genes to enhance autophagy. On the other hand, mutant p53 prevents autophagy. The positive regulations are shown in blue arrows, and the negative regulations are shown in red T-bar lines. Double membrane structure describes an autophagosome containing cellular contents such as proteins, DNA, RNA, lipids, and small organelles that will be digested after fusion of autophagosome with lysosome. MDMX; mouse double minute X, SIRT1: sirtuin 1, AMPK: AMP-activated protein kinase, mTOR: mechanistic target of rapamycin, ULK: Unc-51-like kinase ERK: extracellular signal-related kinase, JNK: c-Jun N-terminal kinase, smARF: the short form of ARF, DRAM: damage-regulated autophagy modulator, DAPK1: death-associated protein kinase 1, BAD: BCL2 associated agonist of cell death, PUMA: p53 upregulated modulator of apoptosis, TGM2: transglutaminase 2, BNIP3: BCL2 interacting protein 3, BAX: BCL-2-associated X protein, ATG: autophagy protein, UVRAG: UV radiation resistance associated gene.

Figure 4

Involvements of p53 and p63 in diabetes. Activation of p53 can contribute to the development of insulin resistance and diabetes, whereas p63 prevents insulin resistance by inducing multiple target genes. The positive regulations are shown in blue arrows, and the negative regulations are shown in red T-bar lines. ROS: reactive oxygen species, NOX2; NADPH oxidase 2, IFNγ: interferon gamma, TNFα: tumor necrosis factor alpha, LKB1: liver kinase B1, SEMA3E: semaphorin 3E, ARF-BP1: ARF-Binding Protein 1, TCF7L2: T-cell factor 7-like 2.