Reactome | TP53 Regulates Metabolic Genes

TP53 Regulates Metabolic Genes

Stable Identifier

R-HSA-5628897

DOI

10.3180/react_355328.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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
9926927	PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes Velasco-Miguel, S, Buckbinder, L, Jean, P, Gelbert, L, Talbott, R, Laidlaw, J, Seizinger, B, Kley, N	Oncogene	1999
16728594	p53 regulates mitochondrial respiration Matoba, S, Kang, JG, Patino, WD, Wragg, A, Boehm, M, Gavrilova, O, Hurley, PJ, Bunz, F, Hwang, PM	Science	2006
18198340	Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling DeYoung, MP, Horak, P, Sofer, A, Sgroi, D, Ellisen, LW	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 Cam, M, Bid, HK, Xiao, L, Zambetti, GP, Houghton, PJ, Cam, H	J. Biol. Chem.	2014
19822145	Role of sestrin2 in peroxide signaling in macrophages Essler, S, Dehne, N, Brüne, B	FEBS Lett.	2009
16839880	TIGAR, a p53-inducible regulator of glycolysis and apoptosis Bensaad, K, Tsuruta, A, Selak, MA, Vidal, MN, Nakano, K, Bartrons, R, Gottlieb, E, Vousden, KH	Cell	2006
13298683	On the origin of cancer cells WARBURG, O	Science	1956
11545734	Regulation of PTEN transcription by p53 Stambolic, V, MacPherson, D, Sas, D, Lin, Y, Snow, B, Jang, Y, Benchimol, S, Mak, TW	Mol. Cell	2001
12203114	Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability Budanov, AV, Shoshani, T, Faerman, A, Zelin, E, Kamer, I, Kalinski, H, Gorodin, S, Fishman, A, Chajut, A, Einat, P, Skaliter, R, Gudkov, AV, Chumakov, PM, Feinstein, E	Oncogene	2002
18344994	Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses Papadia, S, Soriano, FX, Léveillé, F, Martel, MA, Dakin, KA, Hansen, HH, Kaindl, A, Sifringer, M, Fowler, J, Stefovska, V, McKenzie, G, Craigon, M, Corriveau, R, Ghazal, P, Horsburgh, K, Yankner, BA, Wyllie, DJ, Ikonomidou, C, Hardingham, GE	Nat. Neurosci.	2008
23484829	Increased oxidative metabolism in the Li-Fraumeni syndrome Wang, PY, Ma, W, Park, JY, Celi, FS, Arena, R, Choi, JW, Ali, QA, Tripodi, DJ, Zhuang, J, Lago, CU, Strong, LC, Talagala, SL, Balaban, RS, Kang, JG, Hwang, PM	N. Engl. J. Med.	2013
10716435	A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage Tanaka, H, Arakawa, H, Yamaguchi, T, Shiraishi, K, Fukuda, S, Matsui, K, Takei, Y, Nakamura, Y	Nature	2000
15665293	Glycolytic enzymes can modulate cellular life span Kondoh, H, Lleonart, ME, Gil, J, Wang, J, Degan, P, Peters, G, Martinez, D, Carnero, A, Beach, D	Cancer Res.	2005
22682249	Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence Li, T, Kon, N, Jiang, L, Tan, M, Ludwig, T, Zhao, Y, Baer, RJ, Gu, W	Cell	2012
17486094	Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion Bourdon, A, Minai, L, Serre, V, Jais, JP, Sarzi, E, Aubert, S, Chrétien, D, de Lonlay, P, Paquis-Flucklinger, V, Arakawa, H, Nakamura, Y, Munnich, A, Rötig, A	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 Brynczka, C, Labhart, P, Merrick, BA	BMC Genomics	2007
12453409	REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species Ellisen, LW, Ramsayer, KD, Johannessen, CM, Yang, A, Beppu, H, Minda, K, Oliner, JD, McKeon, F, Haber, DA	Mol. Cell	2002
19696408	p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content Park, JY, Wang, PY, Matsumoto, T, Sung, HJ, Ma, W, Choi, JW, Anderson, SA, Leary, SC, Balaban, RS, Kang, JG, Hwang, PM	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 Kawauchi, K, Araki, K, Tobiume, K, Tanaka, N	Nat. Cell Biol.	2008
20378837	Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function Hu, W, Zhang, C, Wu, R, Sun, Y, Levine, A, Feng, Z	Proc. Natl. Acad. Sci. U.S.A.	2010
11959846	p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas Singh, B, Reddy, PG, Goberdhan, A, Walsh, C, Dao, S, Ngai, I, Chou, TC, O-Charoenrat, P, Levine, AJ, Rao, PH, Stoffel, A	Genes Dev.	2002
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 Feng, Z, Hu, W, de Stanchina, E, Teresky, AK, Jin, S, Lowe, S, Levine, AJ	Cancer Res.	2007
15105503	Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD Budanov, AV, Sablina, AA, Feinstein, E, Koonin, EV, Chumakov, PM	Science	2004
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
20399660	The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein Feng, Z, Levine, AJ	Trends Cell Biol.	2010
22864287	PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53 Cui, G, Park, S, Badeaux, AI, Kim, D, Lee, J, Thompson, JR, Yan, F, Kaneko, S, Yuan, Z, Botuyan, MV, Bedford, MT, Cheng, JQ, Mer, G	Nat. Struct. Mol. Biol.	2012