TP53 Regulates Metabolic Genes

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Homo sapiens
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While the p53 tumor suppressor protein (TP53) is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism to prevent tumor development. TP53 regulates transcription of many genes involved in the metabolism of carbohydrates, nucleotides and amino acids, protein synthesis and aerobic respiration.

TP53 stimulates transcription of TIGAR, a D-fructose 2,6-bisphosphatase. TIGAR activity decreases glycolytic rate and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006). TP53 may also negatively regulate the rate of glycolysis by inhibiting the expression of glucose transporters GLUT1, GLUT3 and GLUT4 (Kondoh et al. 2005, Schwartzenberg-Bar-Yoseph et al. 2004, Kawauchi et al. 2008).

TP53 negatively regulates several key points in PI3K/AKT signaling and downstream mTOR signaling, decreasing the rate of protein synthesis and, hence, cellular growth. TP53 directly stimulates transcription of the tumor suppressor PTEN, which acts to inhibit PI3K-mediated activation of AKT (Stambolic et al. 2001). TP53 stimulates transcription of sestrin genes, SESN1, SESN2, and SESN3 (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007). One of sestrin functions may be to reduce and reactivate overoxidized peroxiredoxin PRDX1, thereby reducing ROS levels (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009). Another function of sestrins is to bind the activated AMPK complex and protect it from AKT-mediated inactivation. By enhancing AMPK activity, sestrins negatively regulate mTOR signaling (Budanov and Karin 2008, Cam et al. 2014). The expression of DDIT4 (REDD1), another negative regulator of mTOR signaling, is directly stimulated by TP63 and TP53. DDIT4 prevents AKT-mediated inactivation of TSC1:TSC2 complex, thus inhibiting mTOR cascade (Cam et al. 2014, Ellisen et al. 2002, DeYoung et al. 2008). TP53 may also be involved, directly or indirectly, in regulation of expression of other participants of PI3K/AKT/mTOR signaling, such as PIK3CA (Singh et al. 2002), TSC2 and AMPKB (Feng et al. 2007).

TP53 regulates mitochondrial metabolism through several routes. TP53 stimulates transcription of SCO2 gene, which encodes a mitochondrial cytochrome c oxidase assembly protein (Matoba et al. 2006). TP53 stimulates transcription of RRM2B gene, which encodes a subunit of the ribonucleotide reductase complex, responsible for the conversion of ribonucleotides to deoxyribonucleotides and essential for the maintenance of mitochondrial DNA content in the cell (Tanaka et al. 2000, Bourdon et al. 2007, Kulawiec et al. 2009). TP53 also transactivates mitochondrial transcription factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance (Park et al. 2009). Finally, TP53 stimulates transcription of the mitochondrial glutaminase GLS2, leading to increased mitochondrial respiration rate and reduced ROS levels (Hu et al. 2010).

The great majority of tumor cells generate energy through aerobic glycolysis, rather than the much more efficient aerobic mitochondrial respiration, and this metabolic change is known as the Warburg effect (Warburg 1956). Since the majority of tumor cells have impaired TP53 function, and TP53 regulates a number of genes involved in glycolysis and mitochondrial respiration, it is likely that TP53 inactivation plays an important role in the metabolic derangement of cancer cells such as the Warburg effect and the concomitant increased tumorigenicity (reviewed by Feng and Levine 2010). On the other hand, some mutations of TP53 in Li-Fraumeni syndrome may result in the retention of its wild-type metabolic activities while losing cell cycle and apoptosis functions (Wang et al. 2013). Consistent with such human data, some mutations of p53, unlike p53 null state, retain the ability to regulate energy metabolism while being inactive in regulating its classic gene targets involved in cell cycle, apoptosis and senescence. Retention of metabolic and antioxidant functions of p53 protects p53 mutant mice from early onset tumorigenesis (Li et al. 2012).

Literature References
PubMed ID Title Journal Year
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Gelbert, L, Laidlaw, J, Talbott, R, Seizinger, B, Buckbinder, L, Jean, P, Kley, N, Velasco-Miguel, S

Oncogene 1999
16728594 p53 regulates mitochondrial respiration

Hwang, PM, Kang, JG, Patino, WD, Gavrilova, O, Boehm, M, Bunz, F, Wragg, A, Hurley, PJ, Matoba, S

Science 2006
18198340 Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling

Horak, P, Sgroi, D, Ellisen, LW, Sofer, A, DeYoung, MP

Genes Dev. 2008
24366874 p53/TAp63 and AKT regulate mammalian target of rapamycin complex 1 (mTORC1) signaling through two independent parallel pathways in the presence of DNA damage

Zambetti, GP, Houghton, PJ, Bid, HK, Cam, H, Xiao, L, Cam, M

J. Biol. Chem. 2014
19822145 Role of sestrin2 in peroxide signaling in macrophages

Dehne, N, Brüne, B, Essler, S

FEBS Lett. 2009
16839880 TIGAR, a p53-inducible regulator of glycolysis and apoptosis

Vidal, MN, Bensaad, K, Selak, MA, Tsuruta, A, Nakano, K, Gottlieb, E, Bartrons, R, Vousden, KH

Cell 2006
13298683 On the origin of cancer cells


Science 1956
11545734 Regulation of PTEN transcription by p53

Stambolic, V, Sas, D, Benchimol, S, Snow, B, Jang, Y, MacPherson, D, Lin, Y, Mak, TW

Mol. Cell 2001
12203114 Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability

Feinstein, E, Gudkov, AV, Chajut, A, Kamer, I, Kalinski, H, Fishman, A, Shoshani, T, Skaliter, R, Budanov, AV, Chumakov, PM, Zelin, E, Einat, P, Faerman, A, Gorodin, S

Oncogene 2002
18344994 Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

Corriveau, R, Stefovska, V, Hardingham, GE, Hansen, HH, Dakin, KA, McKenzie, G, Fowler, J, Martel, MA, Sifringer, M, Kaindl, A, Ikonomidou, C, Ghazal, P, Wyllie, DJ, Craigon, M, Léveillé, F, Yankner, BA, Horsburgh, K, Soriano, FX, Papadia, S

Nat. Neurosci. 2008
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Hwang, PM, Ali, QA, Choi, JW, Arena, R, Wang, PY, Strong, LC, Celi, FS, Kang, JG, Zhuang, J, Park, JY, Lago, CU, Tripodi, DJ, Balaban, RS, Ma, W, Talagala, SL

N. Engl. J. Med. 2013
10716435 A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage

Arakawa, H, Nakamura, Y, Matsui, K, Takei, Y, Shiraishi, K, Fukuda, S, Tanaka, H, Yamaguchi, T

Nature 2000
15665293 Glycolytic enzymes can modulate cellular life span

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Cancer Res. 2005
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Jiang, L, Gu, W, Baer, RJ, Zhao, Y, Ludwig, T, Tan, M, Kon, N, Li, T

Cell 2012
17486094 Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion

Arakawa, H, Munnich, A, Aubert, S, Serre, V, Chrétien, D, Rötig, A, Bourdon, A, Sarzi, E, Minai, L, de Lonlay, P, Nakamura, Y, Jais, JP, Paquis-Flucklinger, V

Nat. Genet. 2007
19439913 p53 regulates mtDNA copy number and mitocheckpoint pathway

Kulawiec, M, Ayyasamy, V, Singh, KK

J Carcinog 2009
17540029 NGF-mediated transcriptional targets of p53 in PC12 neuronal differentiation

Labhart, P, Brynczka, C, Merrick, BA

BMC Genomics 2007
12453409 REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species

Yang, A, Oliner, JD, Minda, K, Ellisen, LW, Haber, DA, McKeon, F, Johannessen, CM, Ramsayer, KD, Beppu, H

Mol. Cell 2002
19696408 p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content

Hwang, PM, Kang, JG, Choi, JW, Wang, PY, Anderson, SA, Park, JY, Leary, SC, Balaban, RS, Ma, W, Matsumoto, T, Sung, HJ

Circ. Res. 2009
18692468 p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling

Budanov, AV, Karin, M

Cell 2008
18391940 p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation

Tanaka, N, Tobiume, K, Kawauchi, K, Araki, K

Nat. Cell Biol. 2008
22864287 PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53

Cui, G, Mer, G, Kaneko, S, Badeaux, AI, Park, S, Yan, F, Bedford, MT, Thompson, JR, Lee, J, Botuyan, MV, Yuan, Z, Cheng, JQ, Kim, D

Nat. Struct. Mol. Biol. 2012
20399660 The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein

Feng, Z, Levine, AJ

Trends Cell Biol. 2010
15059920 The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression

Schwartzenberg-Bar-Yoseph, F, Armoni, M, Karnieli, E

Cancer Res. 2004
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Feinstein, E, Budanov, AV, Chumakov, PM, Koonin, EV, Sablina, AA

Science 2004
17409411 The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways

Teresky, AK, Jin, S, Hu, W, Lowe, S, Feng, Z, Levine, AJ, de Stanchina, E

Cancer Res. 2007
11959846 p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas

O-Charoenrat, P, Walsh, C, Reddy, PG, Chou, TC, Ngai, I, Dao, S, Stoffel, A, Rao, PH, Singh, B, Goberdhan, A, Levine, AJ

Genes Dev. 2002
20378837 Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function

Zhang, C, Hu, W, Sun, Y, Wu, R, Levine, A, Feng, Z

Proc. Natl. Acad. Sci. U.S.A. 2010
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