Energy Metabolism/genetics; Homeostasis/genetics; Humans; Metabolic Diseases/genetics/metabolism/pathology; Neoplasms/genetics/metabolism/pathology; Signal Transduction/genetics; Tumor Suppressor Protein p53/genetics/metabolism; Cancer; Metabolism; Normal tissue homeostasis; p53
Abstract :
[en] BACKGROUND: The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells. SCOPE OF REVIEW: We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases. MAJOR CONCLUSIONS: p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lacroix, Matthieu
Riscal, Romain
Arena, Giuseppe ; Gustave Roussy Cancer Campus, Villejuif, France > INSERM U1030
Linares, Laetitia Karine
Le Cam, Laurent
External co-authors :
yes
Language :
English
Title :
Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer.
Kruiswijk, F., Labuschagne, C.F., Vousden, K.H., p53 in survival, death and metabolichealth: a lifeguard with a licence to kill. Nature Reviews Molecular Cell Biology 16:7 (2015), 393–405.
Labuschagne, C.F., Zani, F., Vousden, K.H., Control of metabolism by p53- Cancer and beyond. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1870:1 (2018), 32–42.
Flöter, J., Kaymak, I., Schulze, A., Regulation of metabolic activity by p53. Metabolites, 7(2), 2017, 21.
Liu, J., Zhang, C., Hu, W., Feng, Z., Tumor suppressor p53 and metabolism. Journal of Molecular Cell Biology 11:4 (2018), 284–292.
Schmidt, V., Nagar, R., Martinez, L., Control of nucleotide metabolism enables mutant p53's oncogenic gain-of-function activity. International Journal of Molecular Sciences, 18(12), 2017, 2759.
Blandino, G., Valenti, F., Sacconi, A., Di Agostino, S., Wild-type and mutant p53 protein in mitochondrial dysfunction: emerging insights in cancer disease. Seminars in Cell & Developmental Biology 18 (2019), 30163–30170.
D'Orazi, G., Cirone, M., Mutant p53 and cellular stress pathways: a criminal alliance that promotes cancer progression. Cancers, 11(5), 2019, 614.
Kamp, W.M., Wang, P.-Y., Hwang, P.M., TP53 mutation, mitochondria and cancer. Current Opinion in Genetics & Development 38 (2016), 16–22.
Schwartzenberg-Bar-Yoseph, F., The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Research 64:7 (2004), 2627–2633.
Kawauchi, K., Araki, K., Tobiume, K., Tanaka, N., p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nature Cell Biology 10:5 (2008), 611–618.
Boidot, R., Vegran, F., Meulle, A., Le Breton, A., Dessy, C., Sonveaux, P., et al. Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Research 72:4 (2012), 939–948.
Bensaad, K., Tsuruta, A., Selak, M.A., Vidal, M.N.C., Nakano, K., Bartrons, R., et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:1 (2006), 107–120.
Zhang, C., Liu, J., Wu, R., Liang, Y., Lin, M., Liu, J., et al. Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD. Oncotarget 5:14 (2014), 5535–5546.
Ros, S., Flöter, J., Kaymak, I., Da Costa, C., Houddane, A., Dubuis, S., et al. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells. Oncogene 36:23 (2017), 3287–3299.
Franklin, D.A., He, Y., Leslie, P.L., Tikunov, A.P., Fenger, N., Macdonald, J.M., et al. p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway. Scientific Reports, 6, 2016, 38067.
Kim, H.-R., Roe, J.-S., Lee, J.-E., Cho, E.-J., Youn, H.-D., p53 regulates glucose metabolism by miR-34a. Biochemical and Biophysical Research Communications 437:2 (2013), 225–231.
Kondoh, H., Lleonart, M.E., Gil, J., Wang, J., Degan, P., Peters, G., et al. Glycolytic enzymes can modulate cellular life span. Cancer Research 65:1 (2005), 177–185.
Contractor, T., Harris, C.R., p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Research 72:2 (2012), 560–567.
Morris, J.P., Yashinskie, J.J., Koche, R., Chandwani, R., Tian, S., Chen, C.-C., et al. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature, 2019, 1–31, 10.1038/s41586-019-1577-5.
Suzuki, S., Tanaka, T., Poyurovsky, M.V., Nagano, H., Mayama, T., Ohkubo, S., et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proceedings of the National Academy of Sciences 107:16 (2010), 7461–7466.
Hu, W., Zhang, C., Wu, R., Sun, Y., Levine, A., Feng, Z., Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proceedings of the National Academy of Sciences 107:16 (2010), 7455–7460.
Liu, Y., He, Y., Jin, A., Tikunov, A.P., Zhou, L., Tollini, L.A., et al. Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation. Proceedings of the National Academy of Sciences 11:23 (2014), E2414–E2422.
Assaily, W., Rubinger, D.A., Wheaton, K., Lin, Y., Ma, W., Xuan, W., et al. ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress. Molecular Cell 44:3 (2011), 491–501.
Sanchez-Macedo, N., Feng, J., Faubert, B., Chang, N., Elia, A., Rushing, E.J., et al. Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model. Cell Death & Differentiation 20:4 (2013), 659–668.
Jiang, D., LaGory, E.L., Brož, D.K., Bieging, K.T., Brady, C.A., Link, N., et al. Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function. Cell Reports 10:7 (2015), 1096–1109.
Matoba, S., Kang, J.G., Patino, W.D., Wragg, A., Boehm, M., Gavrilova, O., et al. p53 regulates mitochondrial respiration. Science 312:5780 (2006), 1650–1653.
Park, J.Y., Wang, P.Y., Matsumoto, T., Sung, H.J., Ma, W., Choi, J.W., et al. p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content. Circulation Research 105:7 (2009), 705–712.
Stambolsky, P., Weisz, L., Shats, I., Klein, Y., Goldfinger, N., Oren, M., et al. Regulation of AIF expression by p53. Cell Death & Differentiation 13:12 (2006), 2140–2149.
Achanta, G., Sasaki, R., Feng, L., Carew, J.S., Lu, W., Pelicano, H., et al. Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol gamma. The EMBO Journal 24:19 (2005), 3482–3492.
Wong, T.S., Rajagopalan, S., Townsley, F.M., Freund, S.M., Petrovich, M., Loakes, D., et al. Physical and functional interactions between human mitochondrial single-stranded DNA-binding protein and tumour suppressor p53. Nucleic Acids Research 37:2 (2008), 568–581.
Yoshida, Y., Izumi, H., Torigoe, T., Ishiguchi, H., Itoh, H., Kang, D., et al. P53 physically interacts with mitochondrial transcription factor A and differentially regulates binding to damaged DNA. Cancer Research 63:13 (2003), 3729–3734.
Bakhanashvili, M., Grinberg, S., Bonda, E., Simon, A.J., Moshitch-Moshkovitz, S., Rahav, G., p53 in mitochondria enhances the accuracy of DNA synthesis. Cell Death & Differentiation 15:12 (2008), 1865–1874.
Bergeaud, M., Mathieu, L., Guillaume, A., Moll, U., Mignotte, B., Le Floch, N., et al. Mitochondrial p53 mediates a transcription-independent regulation of cell respiration and interacts with the mitochondrial F₁F₀-ATP synthase. Cell Cycle 12:17 (2014), 2781–2793.
Saleem, A., Iqbal, S., Zhang, Y., Hood, D.A., Effect of p53 on mitochondrial morphology, import, and assembly in skeletal muscle. The Australian Journal of Pharmacy: Cell Physiology 308:4 (2015), C319–C329.
Kong, B., Wang, Q., Fung, E., Xue, K., Tsang, B.K., p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers. Journal of Biological Chemistry 289:39 (2014), 27134–27145.
Li, J., Donath, S., Li, Y., Qin, D., Prabhakar, B.S., Li, P., miR-30 regulates mitochondrial fission through targeting p53 and the dynamin-related protein-1 pathway. PLoS Genetics, 6(1), 2010, e1000795.
Wang, J.-X., Jiao, J.-Q., Li, Q., Long, B., Wang, K., Liu, J.-P., et al. miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nature Medicine 17:1 (2010), 71–78.
Kitamura, N., Nakamura, Y., Miyamoto, Y., Miyamoto, T., Kabu, K., Yoshida, M., et al. Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. PLoS One, 6(1), 2011, e16060.
Kenzelmann Broz, D., Spano Mello, S., Bieging, K.T., Jiang, D., Dusek, R.L., Brady, C.A., et al. Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes & Development 27:9 (2013), 1016–1031.
Zhang, C., Lin, M., Wu, R., Wang, X., Yang, B., Levine, A.J., et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proceedings of the National Academy of Sciences 108:39 (2011), 16259–16264.
Miyamoto, Y., Kitamura, N., Nakamura, Y., Futamura, M., Miyamoto, T., Yoshida, M., et al. Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control. PLoS One, 6(1), 2011, e16054.
J Jiang, P., Du, W., Wang, X., Mancuso, A., Gao, X., Wu, M., et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nature Cell Biology 13:3 (2011), 310–316.
Goldstein, I., Rotter, V., Regulation of lipid metabolism by p53 – fighting two villains with one sword. Trends in Endocrinology and Metabolism 23:11 (2012), 567–575.
Parrales, A., Iwakuma, T., p53 as a regulator of lipid metabolism in cancer. International Journal of Molecular Sciences, 17(12), 2016, 2074.
Moon, S.-H., Huang, C.-H., Houlihan, S.L., Regunath, K., Freed-Pastor, W.A., Morris, J.P. 4th, et al. p53 represses the mevalonate pathway to mediate tumor suppression. Cell 176:3 (2018), 564–580.
Jiang, P., Du, W., Mancuso, A., Wellen, K.E., Yang, X., Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493:7434 (2013), 689–693.
Deisenroth, C., Itahana, Y., Tollini, L., Jin, A., Zhang, Y., p53-inducible DHRS3 is an endoplasmic reticulum protein associated with lipid droplet accumulation. Journal of Biological Chemistry 286:32 (2011), 28343–28356.
Kirschner, R.D., Rother, K., Müller, G.A., Engeland, K., The retinal dehydrogenase/reductase retSDR1/DHRS3gene is activated by p53 and p63 but not by mutants derived from tumors or EEC/ADULT malformation syndromes. Cell Cycle 9:11 (2014), 2177–2188.
Mirza, A., Wu, Q., Wang, L., McClanahan, T., Bishop, W.R., Gheyas, F., et al. Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression. Oncogene 22:23 (2003), 3645–3654.
Rueda-Rincon, N., Bloch, K., Derua, R., Vyas, R., Harms, A., Hankemeier, T., et al. p53 attenuates AKT signaling by modulating membrane phospholipid composition. Oncotarget 6:25 (2015), 21240–21254.
Kirschner, K., Samarajiwa, S.A., Cairns, J.M., Menon, S., Pérez-Mancera, P.A., Tomimatsu, K., et al. Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53. PLoS Genetics, 11(3), 2015, e1005053.
Moiseeva, O., Bourdeau, V., Roux, A., Deschênes-Simard, X., Ferbeyre, G., Mitochondrial dysfunction contributes to oncogene-induced senescence. Molecular and Cellular Biology 29:16 (2009), 4495–4507.
Quijano, C., Cao, L., Fergusson, M.M., Romero, H., Liu, J., Gutkind, S., et al. Oncogene-induced senescence results in marked metabolic and bioenergetic alterations. Cell Cycle 11:7 (2012), 1383–1392.
Goldstein, I., Ezra, O., Rivlin, N., Molchadsky, A., Madar, S., Goldfinger, N., et al. p53, a novel regulator of lipid metabolism pathways. Journal of Hepatology 56:3 (2012), 656–662.
Ide, T., Brown-Endres, L., Chu, K., Ongusaha, P.P., Ohtsuka, T., El-Deiry, W.S., et al. GAMT, a p53-inducible modulator of apoptosis, is critical for the adaptive response to nutrient stress. Molecular Cell 36:3 (2009), 379–392.
Jeffries, K.A., Krupenko, N.I., Ceramide signaling and p53 pathways. Advances in Cancer Research 140 (2018), 191–215.
Taha, T.A., Osta, W., Kozhaya, L., Bielawski, J., Johnson, K.R., Gillanders, W.E., et al. Down-regulation of sphingosine kinase-1 by DNA damage. Journal of Biological Chemistry 279:19 (2004), 20546–20554.
Heffernan-Stroud, L.A., Helke, K.L., Jenkins, R.W., De Costa, A.-M., Hannun, Y.A., Obeid, L.M., Defining a role for sphingosine kinase 1 in p53-dependent tumors. Oncogene 31:9 (2011), 1166–1175.
Fekry, B., Jeffries, K.A., Esmaeilniakooshkghazi, A., Ogretmen, B., Krupenko, S.A., Krupenko, N.I., CerS6Is a novel transcriptional target of p53 protein activated by non-genotoxic stress. Journal of Biological Chemistry 291:32 (2016), 16586–16596.
Shamseddine, A.A., Clarke, C.J., Carroll, B., Airola, M.V., Mohammed, S., Rella, A., et al. P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin-induced growth arrest. Cell Death & Disease, 6(10), 2015, e1947 10.
Xu, R., Garcia-Barros, M., Wen, S., Li, F., Lin, C.-L., Hannun, Y.A., et al. Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2. Cell Death & Differentiation 25:5 (2018), 841–856.
Fekry, B., Jeffries, K.A., Esmaeilniakooshkghazi, A., Szulc, Z.M., Knagge, K.J., Kirchner, D.R., et al. -ceramide is a natural regulatory ligand of p53 in cellular stress response. Nature Communications, 2018, 1–12, 10.1038/s41467-018-06650-y.
Hoeferlin, L.A., Fekry, B., Ogretmen, B., Krupenko, S.A., Krupenko, N.I., Folate stress induces apoptosis via p53-dependent de Novo ceramide synthesis and up-regulation of ceramide synthase 6. Journal of Biological Chemistry 288:18 (2013), 12880–12890.
Torti, S.V., Torti, F.M., Iron and cancer: more ore to be mined. Nature Reviews Cancer 13:5 (2013), 342–355.
Weizer-Stern, O., Adamsky, K., Margalit, O., Ashur-Fabian, O., Givol, D., Amariglio, N., et al. Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53. British Journal of Haematology 138:2 (2007), 253–262.
Funauchi, Y., Tanikawa, C., Lo, P.H.Y., Mori, J., Daigo, Y., Takano, A., et al. Regulation of iron homeostasis bythe p53-ISCU pathway. Scientific Reports, 2(5), 2015, 16497.
Hwang, P.M., Bunz, F., Yu, J., Rago, C., Chan, T.A., Murphy, M.P., et al. Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nature Medicine 7:10 (2001), 1111–1117.
Liu, G., Chen, X., The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis. Oncogene 21:47 (2002), 7195–7204.
Shimizu, R., Lan, N.N., Tai, T.T., Adachi, Y., Kawazoe, A., Mu, A., et al. p53 directly regulates the transcription of the human frataxin gene and its lack of regulation in tumor cells decreases the utilization of mitochondrial iron. Gene 551:1 (2014), 79–85.
Dongiovanni, P., Fracanzani, A.L., Cairo, G., Megazzini, C.P., Gatti, S., Rametta, R., et al. Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. American Journal Of Pathology 176:2 (2010), 1006–1017.
An, W.G., Kanekal, M., Simon, M.C., Maltepe, E., Blagosklonny, M.V., Neckers, L.M., Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392:6674 (1998), 405–408.
Saletta, F., Suryo Rahmanto, Y., Noulsri, E., Richardson, D.R., Iron chelator-mediated alterations in gene expression: identification of novel iron-regulated molecules that are molecular targets of hypoxia-inducible factor-1 and p53. Molecular Pharmacology 77:3 (2010), 443–458.
Shen, J., Sheng, X., Chang, Z., Wu, Q., Wang, S., Xuan, Z., et al. Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulationof p53 localization, stability, and function. Cell Reports 7:1 (2014), 180–193.
Lee, J.-H., Jang, H., Cho, E.-J., Youn, H.-D., Ferritin binds and activates p53 under oxidative stress. Biochemical and Biophysical Research Communications 389:3 (2009), 399–404.
Zhang, J., Chen, X., p53 tumor suppressor and iron homeostasis. FEBS Journal 286:4 (2018), 620–629.
Zhang, Y., Qian, Y., Zhang, J., Yan, W., Jung, Y.-S., Chen, M., et al. Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. Genes & Development 31:12 (2017), 1243–1256.
Palomo, G.M., Cerrato, T., Gargini, R., Diaz-Nido, J., Silencing of frataxin gene expression triggers p53-dependent apoptosis in human neuron-like cells. Human Molecular Genetics 20:14 (2011), 2807–2822.
Li, T., Kon, N., Jiang, Le, Tan, M., Ludwig, T., Zhao, Y., et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149:6 (2012), 1269–1283.
Jiang, Le, Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., et al. Ferroptosis as a p53-mediated activity during tumor suppression. Nature 520:7545 (2015), 57–62.
Wang, S.-J., Li, D., Ou, Y., Jiang, Le, Chen, Y., Zhao, Y., et al. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression. Cell Reports 17:2 (2016), 366–373.
Wang, Y., Yang, L., Zhang, X., Cui, W., Liu, Y., Sun, Q.R., et al. Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53. EMBO Reports, 2019, e47563.
Chu, B., Kon, N., Chen, D., Li, T., Liu, T., Jiang, Le, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nature Cell Biology 21:5 (2019), 579–591.
Ou, Y., Wang, S.-J., Li, D., Chu, B., Gu, W., Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proceedings of the National Academy of Sciences 113:44 (2016), E6806–E6812.
Jennis, M., Kung, C.-P., Basu, S., Budina-Kolomets, A., Leu, J.I.-J., Khaku, S., et al. An African-specific polymorphism in the TP53gene impairs p53 tumor suppressor function in a mouse model. Genes & Development 30:8 (2016), 918–930.
Xie, Y., Zhu, S., Song, X., Sun, X., Fan, Y., Liu, J., et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Reports 20:7 (2017), 1692–1704.
Tarangelo, A., Magtanong, L., Bieging-Rolett, K.T., Li, Y., Ye, J., Attardi, L.D., et al. p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Reports 22:3 (2018), 569–575.
Jones, R.G., Plas, D.R., Kubek, S., Buzzai, M., Mu, J., Xu, Y., et al. AMP-Activated Protein Kinase induces a p53-dependent Metabolic checkpoint. Molecular Cell 18:3 (2005), 283–293.
Reid, M.A., Wang, W.-I., Rosales, K.R., Welliver, M.X., Pan, M., Kong, M., The B55a subunit of PP2A Drivesa p53-dependent metabolic adaptation to glutamine deprivation. Molecular Cell 50:2 (2013), 200–211.
Maddocks, O.D.K., Berkers, C.R., Mason, S.M., Zheng, L., Blyth, K., Gottlieb, E., et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493:7433 (2013), 542–546.
Tajan, M., Hock, A.K., Blagih, J., Robertson, N.A., Labuschagne, C.F., Kruiswijk, F., et al. A role for p53 in the adaptation to glutamine starvation through the expression of SLC1A3. Cell Metabolism 28:5 (2018), 721–736.
Lowman, X.H., Hanse, E.A., Yang, Y., Gabra, M.B.I., Tran, T.Q., Li, H., et al. p53 promotes cancer cell adaptation to glutamine deprivation by upregulating Slc7a3 to increase arginine uptake. Cell Reports 26:11 (2019), 3051–3054.
Ou, Y., Wang, S.-J., Jiang, L., Zheng, B., Gu, W., p53 protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. Journal of Biological Chemistry 290:1 (2015), 457–466.
Riscal, R., Schrepfer, E., Arena, G., Cissé, M.Y., Bellvert, F., Heuillet, M., et al. Chromatin-bound MDM2 regulates serine metabolism and redox homeostasis independently of p53. Molecular Cell 62:6 (2016), 890–902.
Phang, J.M., Proline metabolism in cell regulation and cancer biology: recent advances and hypotheses. Antioxidants and Redox Signaling 30:4 (2019), 635–649.
Yoon, K.-A., Nakamura, Y., Arakawa, H., Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. Journal of Human Genetics 49:3 (2004), 134–140.
Polyak, K., Xia, Y., Zweier, J.L., Kinzler, K.W., Vogelstein, B., A model for p53-induced apoptosis. Nature 389:6648 (1997), 300–305.
Raimondi, I., Ciribilli, Y., Monti, P., Bisio, A., Pollegioni, L., Fronza, G., et al. P53 family members modulate the expression of PRODH, but not PRODH2, via intronic p53 response elements. PLoS One, 8(7), 2013, e69152.
Wei, C.-L., Wu, Q., Vega, V.B., Chiu, K.P., Ng, P., Zhang, T., et al. A global map of p53 transcription-factor binding sites in the human genome. Cell 124:1 (2006), 207–219, 10.1016/j.cell.2005.10.043.
Donald, S.P., Sun, X.Y., Hu, C.A., Yu, J., Mei, J.M., Valle, D., et al. Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species. Cancer Research 61:5 (2001), 1810–1815.
Nagano, T., Nakashima, A., Onishi, K., Kawai, K., Awai, Y., Kinugasa, M., et al. Proline dehydrogenase promotes senescence through the generation of reactive oxygen species. Journal of Cell Science 130:8 (2017), 1413–1420.
Pang, S., Lynn, D.A., Lo, J.Y., Paek, J., Curran, S.P., SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation. Nature Communications, 5, 2014, 5048.
Le, Li, Mao, Y., Zhao, L., Li, L., Wu, J., Zhao, M., et al. p53 regulation of ammonia metabolism throughurea cycle controls polyamine biosynthesis. Nature 567:7747 (2019), 253–256.
Kim, H.-R., Roe, J.-S., Lee, J.-E., Hwang, I.-Y., Cho, E.-J., Youn, H.-D., A p53-inducible microRNA-34a downregulates Ras signaling by targeting IMPDH. Biochemical and Biophysical Research Communications 418:4 (2012), 682–688.
Holzer, K., Drucker, E., Roessler, S., Dauch, D., Heinzmann, F., Waldburger, N., et al. Proteomic Analysis Reveals GMP Synthetase as p53 repression taarget in liver cancer. American Journal Of Pathology 187:2 (2017), 228–235.
Reddy, B.A., van der Knaap, J.A., Bot, A.G.M., Mohd-Sarip, A., Dekkers, D.H.W., Timmermans, M.A., et al. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Molecular Cell 53:3 (2014), 458–470.
Wilson, P.M., Fazzone, W., LaBonte, M.J., Lenz, H.-J., Ladner, R.D., Regulation of human dUTPase gene expression and p53-mediated transcriptional repression in response to oxaliplatin-induced DNA damage. Nucleic Acids Research 37:1 (2008), 78–95.
Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404:6773 (2000), 42–49.
Nakano, K., Bálint, E., Ashcroft, M., Vousden, K.H., A ribonucleotide reductase gene is a transcriptional target of p53 and p73. Oncogene 19:37 (2000), 4283–4289.
He, Z., Hu, X., Liu, W., Dorrance, A., Garzon, R., Houghton, P.J., et al. P53 suppresses ribonucleotide reductase via inhibiting mTORC1. Oncotarget 8:25 (2017), 41422–41431.
Sablina, A.A., Budanov, A.V., Ilyinskaya, G.V., Agapova, L.S., Kravchenko, J.E., Chumakov, P.M., The antioxidant function of the p53 tumor suppressor. Nature Medicine 11:12 (2005), 1306–1313.
Matheu, A., Maraver, A., Klatt, P., Flores, I., Garcia-Cao, I., Borras, C., et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448:7151 (2007), 375–379.
Forrester, K., Ambs, S., Lupold, S.E., Kapust, R.B., Spillare, E.A., Weinberg, W.C., et al. Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53. Proceedings of the National Academy of Sciences of the United States of America 93:6 (1996), 2442–2447.
Hussain, S.P., Amstad, P., He, P., Robles, A., Lupold, S., Kaneko, I., et al. p53-Induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Research 64:7 (2004), 2350–2356.
Kang, M.Y., Kim, H.-B., Piao, C., Lee, K.H., Hyun, J.W., Chang, I.-Y., et al. The critical role of catalase in prooxidant and antioxidant function of p53. Cell Death & Differentiation 20:1 (2012), 117–129.
O'Connor, J.C., Wallace, D.M., O'Brien, C.J., Cotter, T.G., A novel antioxidant function for the tumor-suppressor gene p53 in the retinal ganglion cell. Investigative Ophthalmology & Visual Science 49:10 (2008), 4237–4244.
Velasco-Miguel, S., Buckbinder, L., Jean, P., Gelbert, L., Talbott, R., Laidlaw, J., et al. PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene 18:1 (1999), 127–137.
Budanov, A.V., Shoshani, T., Faerman, A., Zelin, E., Kamer, I., Kalinski, H., et al. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 21:39 (2002), 6017–6031.
Budanov, A.V., Karin, M., p53 target genes Sestrin1 and Sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:3 (2008), 451–460.
Bae, S.H., Sung, S.H., Oh, S.Y., Lim, J.M., Lee, S.K., Park, Y.N., et al. Sestrins activate Nrf2 by promoting p62-dependent autophagic Degradationof Keap1 and prevent oxidative liver damage. Cell Metabolism 17:1 (2013), 73–84.
Tomasini, R., Samir, A.A., Pebusque, M.-J., Calvo, E.L., Totaro, S., Dagorn, J.C., et al. P53-dependent expression of the stress-induced protein (SIP). European Journal of Cell Biology 81:5 (2002), 294–301.
N'guessan, P., Pouyet, L., Gosset, G., Hamlaoui, S., Seillier, M., Cano, C.E., et al. Absence of tumor suppressor tumor protein 53-induced nuclear protein 1 (TP53INP1) sensitizes mouse thymocytes and embryonic fibroblasts to redox-driven apoptosis. Antioxidants and Redox Signaling 15:6 (2011), 1639–1653.
Itahana, Y., Han, R., Barbier, S., Lei, Z., Rozen, S., Itahana, K., The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense. Oncogene 34:14 (2014), 1799–1810.
Italiano, D., Lena, A.M., Melino, G., Candi, E., Identification of NCF2/p67phox as a novel p53 target gene. Cell Cycle 11:24 (2014), 4589–4596.
Dhar, S.K., Xu, Y., Chen, Y., St Clair, D.K., Specificity protein 1-dependent p53-mediated suppression of human manganese superoxide dismutase gene expression. Journal of Biological Chemistry 281:31 (2006), 21698–21709.
Zhao, Y., Chaiswing, L., Velez, J.M., Batinic-Haberle, I., Colburn, N.H., Oberley, T.D., et al. p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase. Cancer Research 65:9 (2005), 3745–3750.
Trinei, M., Giorgio, M., Cicalese, A., Barozzi, S., Ventura, A., Migliaccio, E., et al. A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene 21:24 (2002), 3872–3878.
Guo, X., Disatnik, M.-H., Monbureau, M., Shamloo, M., Mochly-Rosen, D., Qi, X., Inhibition of mitochondrial fragmentation diminishes Huntington's disease–associated neurodegeneration. Journal of Clinical Investigation 123:12 (2013), 5371–5388.
Marchenko, N.D., Zaika, A., Moll, U.M., Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. Journal of Biological Chemistry 275:21 (2000), 16202–16212.
Leu, J.I.-J., Dumont, P., Hafey, M., Murphy, M.E., George, D.L., Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex. Nature Cell Biology 6:5 (2004), 443–450.
Eriksson, S.E., Ceder, S., Bykov, V.J.N., Wiman, K.G., p53 as a hub in cellular redox regulation and therapeutic target in cancer. Journal of Molecular Cell Biology 11:4 (2019), 330–341.
Hafsi, H., Hainaut, P., Redox control and interplay between p53 isoforms: roles in the regulation of basal p53 levels, cell fate, and senescence. Antioxidants and Redox Signaling 15:6 (2011), 1655–1667.
Maillet, A., Pervaiz, S., Redox regulation of p53, redox effectors regulated by p53: a subtle balance. Antioxidants and Redox Signaling 16:11 (2012), 1285–1294.
Niwa-Kawakita, M., Ferhi, O., Soilihi, H., Le Bras, M., Lallemand-Breitenbach, V., de Thé, H., PML is a ROS sensor activating p53 upon oxidative stress. Journal of Experimental Medicine 214:11 (2017), 3197–3206.
Tessier, S., Martin-Martin, N., de Thé, H., Carracedo, A., Lallemand-Breitenbach, V., Promyelocytic leukemia protein, a protein at the crossroad of oxidative stress and metabolism. Antioxidants and Redox Signaling 26:9 (2017), 432–444.
De Stanchina, E., Querido, E., Narita, M., Davuluri, R.V., Pandolfi, P.P., Ferbeyre, G., et al. PML is a direct p53 target that modulates p53 effector functions. Molecular Cell 13:4 (2004), 523–535.
Vaseva, A.V., Marchenko, N.D., Ji, K., Tsirka, S.E., Holzmann, S., Moll, U.M., p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149:7 (2012), 1536–1548.
Eby, K.G., Rosenbluth, J.M., Mays, D.J., Marshall, C.B., Barton, C.E., Sinha, S., et al. ISG20L1 is a p53 family target gene that modulates genotoxic stress-induced autophagy. Molecular Cancer, 9(1), 2010, 95.
Gao, W., Shen, Z., Shang, L., Wang, X., Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death. Cell Death & Differentiation 18:10 (2011), 1598–1607.
Crighton, D., Wilkinson, S., O'Prey, J., Syed, N., Smith, P., Harrison, P.R., et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126:1 (2006), 121–134.
Martoriati, A., Doumont, G., Alcalay, M., Bellefroid, E., Pelicci, P.G., Marine, J.-C., dapk1, encoding an activator of a p19ARF-p53-mediated apoptotic checkpoint, is a transcription target of p53. Oncogene 24:8 (2004), 1461–1466.
Feng, Z., Zhang, H., Levine, A.J., Jin, S., The coordinate regulation of the p53 and mTOR pathways in cells. Proceedings of the National Academy of Sciences of the United States of America 102:23 (2005), 8204–8209.
Tasdemir, E., Maiuri, M.C., Galluzzi, L., Vitale, I., Djavaheri-Mergny, M., D'Amelio, M., et al. Regulation of autophagy by cytoplasmic p53. Nature Cell Biology 10:6 (2008), 676–687.
Tavernarakis, N., Pasparaki, A., Tasdemir, E., Maiuri, M.C., Kroemer, G., The effects of p53 on whole organism longevity are mediated by autophagy. Autophagy 4:7 (2014), 870–873.
Lee, I.H., Kawai, Y., Fergusson, M.M., Rovira, I.I., Bishop, A.J.R., Motoyama, N., et al. Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science 336:6078 (2012), 225–228.
Huo, Y., Cai, H., Teplova, I., Bowman-Colin, C., Chen, G., Price, S., et al. Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer. Cancer Discovery 3:8 (2013), 894–907.
Guo, J.Y., Karsli-Uzunbas, G., Mathew, R., Aisner, S.C., Kamphorst, J.J., Strohecker, A.M., et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes & Development 27:13 (2013), 1447–1461.
Rosenfeldt, M.T., O'Prey, J., Morton, J.P., Nixon, C., Mackay, G., Mrowinska, A., et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504:7479 (2013), 296–300.
Okoshi, R., Ozaki, T., Yamamoto, H., Ando, K., Koida, N., Ono, S., et al. Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. Journal of Biological Chemistry 283:7 (2008), 3979–3987.
Imamura, K., Ogura, T., Kishimoto, A., Kaminishi, M., Esumi, H., Cell cycle regulation via p53 phosphorylation by a 5′-AMP activated protein kinase activator, 5-aminoimidazole- 4-Carboxamide-1-β–Ribofuranoside, in a human hepatocellular carcinoma cell line. Biochemical and Biophysical Research Communications 287:2 (2001), 562–567.
Armata, H.L., Golebiowski, D., Jung, D.Y., Ko, H.J., Kim, J.K., Sluss, H.K., Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis. Molecular and Cellular Biology 30:24 (2010), 5787–5794.
Feng, Z., Hu, W., de Stanchina, E., Teresky, A.K., Jin, S., Lowe, S., et al. 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. Cancer Research 67:7 (2007), 3043–3053.
Co, N.N., Iglesias, D., Celestino, J., Kwan, S.Y., Mok, S.C., Schmandt, R., et al. Loss of LKB1 in high-grade endometrial carcinoma: LKB1 is a novel transcriptional target of p53. Cancer 120:22 (2014), 3457–3468.
Pappas, K., Xu, J., Zairis, S., Resnick-Silverman, L., Abate, F., Steinbach, N., et al. p53 maintains baseline expression of multiple tumor suppressor genes. Molecular Cancer Research 15:8 (2017), 1051–1062.
Cam, M., Bid, H.K., Xiao, L., Zambetti, G.P., Houghton, P.J., Cam, H., p53/TAp63 and AKT regulate mammalian target of rapamycin complex 1 (mTORC1) signaling through two independent parallel pathways in the presence of DNA damage. Journal of Biological Chemistry 289:7 (2014), 4083–4094.
Ellisen, L.W., Ramsayer, K.D., Johannessen, C.M., Yang, A., Beppu, H., Minda, K., et al. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Molecular Cell 10:5 (2002), 995–1005.
Stambolic, V., MacPherson, D., Sas, D., Lin, Y., Snow, B., Jang, Y., et al. Regulation of PTEN transcription by p53. Molecular Cell 8:2 (2001), 317–325.
Buckbinder, L., Talbott, R., Velasco-Miguel, S., Takenaka, I., Faha, B., Seizinger, B.R., et al. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377:6550 (1995), 646–649.
Kawase, T., Ohki, R., Shibata, T., Tsutsumi, S., Kamimura, N., Inazawa, J., et al. PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell 136:3 (2009), 535–550.
Webster, N.J., Resnik, J.L., Reichart, D.B., Strauss, B., Haas, M., Seely, B.L., Repression of the insulin receptor promoter by the tumor suppressor gene product p53: a possible mechanism for receptor overexpression in breast cancer. Cancer Research 56:12 (1996), 2781–2788.
Ashcroft, M., Ludwig, R.L., Woods, D.B., Copeland, T.D., Weber, H.O., MacRae, E.J., et al. Phosphorylation of HDM2 by Akt. Oncogene 21:13 (2002), 1955–1962.
Chen, D., Li, M., Luo, J., Gu, W., Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. Journal of Biological Chemistry 278:16 (2003), 13595–13598.
Alarcon, R., Koumenis, C., Geyer, R.K., Maki, C.G., Giaccia, A.J., Hypoxia induces p53 accumulation through MDM2 down-regulation and inhibition of E6-mediated degradation. Cancer Research 59:24 (1999), 6046–6051.
Zhu, Y., Mao, X.O., Sun, Y., Xia, Z., Greenberg, D.A., p38 mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in Neurons. Journal of Biological Chemistry 277:25 (2002), 22909–22914.
Lee, S.-J., Lim, C.-J., Min, J.-K., Lee, J.-K., Kim, Y.-M., Lee, J.-Y., et al. Protein phosphatase 1 nuclear targeting subunit is a hypoxia inducible gene: its role in post-translational modification of p53 and MDM2. Cell Death & Differentiation 14:6 (2007), 1106–1116.
Galban, S., Martindale, J.L., Mazan-Mamczarz, K., Lopez de Silanes, I., Fan, J., Wang, W., et al. Influence of the RNA-binding protein HuR in pVHL-regulated p53 expression in renal carcinoma cells. Molecular and Cellular Biology 23:20 (2003), 7083–7095.
Hammond, E.M., Denko, N.C., Dorie, M.J., Abraham, R.T., Giaccia, A.J., Hypoxia links ATR and p53 through replication arrest. Molecular and Cellular Biology 22:6 (2002), 1834–1843.
Chandel, N.S., Vander Heiden, M.G., Thompson, C.B., Schumacker, P.T., Redox regulation of p53 during hypoxia. Oncogene 19:34 (2000), 3840–3848.
Schmaltz, C., Hardenbergh, P.H., Wells, A., Fisher, D.E., Regulation of proliferation-survival decisions during tumor cell hypoxia. Molecular and Cellular Biology 18:5 (1998), 2845–2854.
Thomas, L.W., Ashcroft, M., Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria. Cellular and Molecular Life Sciences 76:9 (2019), 1759–1777.
Sermeus, A., Michiels, C., Reciprocal influence of the p53 and the hypoxic pathways. Cell Death & Disease, 2(5), 2011, e164 11.
Humpton, T.J., Vousden, K.H., Regulation of cellular metabolism and hypoxia by p53. Cold Spring Harbor Perspectives in Medicine, 6(7), 2016, a026146.
Al Tameemi, W., Dale, T.P., Al-Jumaily, R.M.K., Forsyth, N.R., Hypoxia-modified cancer cell metabolism. Frontiers of Cell & Developmental Biology, 7, 2019, 4.
Hammond, E.M., Mandell, D.J., Salim, A., Krieg, A.J., Johnson, T.M., Shirazi, H.A., et al. Genome-wide analysis of p53 under hypoxic conditions. Molecular and Cellular Biology 26:9 (2006), 3492–3504.
Xenaki, G., Ontikatze, T., Rajendran, R., Stratford, I.J., Dive, C., Krstic-Demonacos, M., et al. PCAF is an HIF-1α cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene 27:44 (2008), 5785–5796.
Koumenis, C., Alarcon, R., Hammond, E., Sutphin, P., Hoffman, W., Murphy, M., et al. Regulation of p53 by hypoxia: Dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Molecular and Cellular Biology 21:4 (2001), 1297–1310.
Wang, E.Y., Gang, H., Aviv, Y., Dhingra, R., Margulets, V., Kirshenbaum, L.A., p53 mediates autophagy and cell death by a mechanism contingent on Bnip3. Hypertension 62:1 (2013), 70–77.
Fei, P., Wang, W., Kim, S.-H., Wang, S., Burns, T.F., Sax, J.K., et al. Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. Cancer Cell 6:6 (2004), 597–609.
Ito, A., Kawaguchi, Y., Lai, C.-H., Kovacs, J.J., Higashimoto, Y., Appella, E., et al. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. The EMBO Journal 21:22 (2002), 6236–6245.
Barlev, N.A., Liu, L., Chehab, N.H., Mansfield, K., Harris, K.G., Halazonetis, T.D., et al. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Molecular Cell 8:6 (2001), 1243–1254.
Hua, W.-K., Qi, J., Cai, Q., Carnahan, E., Ayala Ramirez, M., Li, L., et al. HDAC8 regulates long-term hematopoietic stem-cell maintenance under stress by modulating p53 activity. Blood 130:24 (2017), 2619–2630.
Yan, W., Liu, S., Xu, E., Zhang, J., Zhang, Y., Chen, X., et al. Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Oncogene 32:5 (2012), 599–609.
Zhao, S., Xu, W., Jiang, W., Yu, W., Lin, Y., Zhang, T., et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327:5968 (2010), 1000–1004.
Kim, S.C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Molecular Cell 23:4 (2006), 607–618.
McLure, K.G., Takagi, M., Kastan, M.B., NAD+ Modulates p53 DNA Binding Specificity and cellular reprogramming. Molecular and Cellular Biology 24:22 (2004), 9958–9967.
Ong, A.L.C., Ramasamy, T.S., Role of Sirtuin 1-p53 regulatory axis in aging, cancer and Ageing. Ageing Research Reviews 43 (2018), 64–80.
Cheng, H.-L., Mostoslavsky, R., Saito, S., Manis, J.P., Gu, Y., Patel, P., et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 100:19 (2003), 10794–10799.
Wang, Q., Zhang, Y., Yang, C., Xiong, H., Lin, Y., Yao, J., et al. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Proceedings of the National Academy of Sciences of the United States of America 103:5968 (2010), 10230–10235.
Nemoto, S., Fergusson, M.M., Finkel, T., Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 306:5704 (2004), 2105–2108.
Naqvi, A., Hoffman, T.A., DeRicco, J., Kumar, A., Kim, C.-S., Jung, S.-B., et al. A single-nucleotide variation in a p53-binding site affects nutrient-sensitive human SIRT1 expression. Human Molecular Genetics 19:21 (2010), 4123–4133.
Yamakuchi, M., Ferlito, M., Lowenstein, C.J., miR-34a repression of SIRT1 regulates apoptosis. Proceedings of the National Academy of Sciences 105:36 (2008), 13421–13426.
Amano, H., Chaudhury, A., Rodriguez-Aguayo, C., Lu, L., Akhanov, V., Catic, A., et al. Telomere dysfunction induces sirtuin repression that drives telomere-dependent disease. Cell Metabolism 29:6 (2019), 1274–1279.
Sahin, E., Colla, S., Liesa, M., Moslehi, J., Müller, F.L., Guo, M., et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470:7334 (2011), 359–365.
Sen, N., Satija, Y.K., Das, S., PGC-1α, a key modulator of p53, promotes cell survival upon metabolic stress. Molecular Cell 44:4 (2011), 621–634.
Hallenborg, P., Fjære, E., Liaset, B., Petersen, R.K., Murano, I., Sonne, S.B., et al. p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α. American Journal of Physiology-Endocrinology and Metabolism 310:2 (2016), E116–E128.
Saleem, A., Adhihetty, P.J., Hood, D.A., Role of p53 in mitochondrial biogenesis and apoptosis in skeletal muscle. Physiological Genomics 37:1 (2009), 58–66.
Saleem, A., Hood, D.A., Acute exercise induces tumour suppressor protein p53 translocation to the mitochondria and promotes a p53-Tfam-mitochondrial DNA complex in skeletal muscle. The Journal of Physiology 591:14 (2013), 3625–3636.
Safdar, A., Khrapko, K., Flynn, J.M., Saleem, A., Lisio, M., Johnston, A.P.W., et al. Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice. Skeletal Muscle, 2016, 1–18.
Beyfuss, K., Hood, D.A., A systematic review of p53 regulation of oxidative stress in skeletal muscle. Redox Report 23:1 (2018), 100–117.
Mak, T.W., Hauck, L., Grothe, D., Billia, F., p53 regulates the cardiac transcriptome. Proceedings of the National Academy of Sciences 114:9 (2017), 2331–2336.
Gogna, R., Madan, E., Khan, M., Pati, U., Kuppusamy, P., p53's choice of myocardial death or survival: oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53-Lys 118acetylation. EMBO Molecular Medicine 5:11 (2013), 1662–1683.
Krstic, J., Galhuber, M., Schulz, T., Schupp, M., Prokesch, A., p53 as a Dichotomous regulator of liver disease: the dose makes the medicine. International Journal of Molecular Sciences, 19(3), 2018, 921.
Prokesch, A., Graef, F.A., Madl, T., Kahlhofer, J., Heidenreich, S., Schumann, A., et al. Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis. The FASEB Journal 31:2 (2017), 732–742.
Yahagi, N., Shimano, H., Matsuzaka, T., Sekiya, M., Najima, Y., Okazaki, S., et al. p53 involvement in the pathogenesis of fatty liver disease. Journal of Biological Chemistry 279:20 (2004), 20571–20575.
Homayounfar, R., Jeddi-Tehrani, M., Cheraghpour, M., Ghorbani, A., Zand, H., Relationship of p53 accumulation in peripheral tissues of high-fat diet-induced obese rats with decrease in metabolic and oncogenic signaling of insulin. General and Comparative Endocrinology 214:C (2015), 134–139.
Kim, J., Yu, L., Chen, W., Xu, Y., Wu, M., Todorova, D., et al. Wild-type p53 promotes cancer metabolic switch by inducing PUMA-dependent suppression of oxidative phosphorylation. Cancer Cell 35:2 (2019), 191–198.
Zhang, P., Tu, B., Wang, H., Cao, Z., Tang, M., Zhang, C., et al. Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proceedings of the National Academy of Sciences 111:29 (2014), 10684–10689.
Wang, S.-J., Yu, G., Jiang, L., Li, T., Lin, Q., Tang, Y., et al. p53-dependent regulation of metabolic function through transcriptional activation of pantothenate kinase-1 gene. Cell Cycle 12:5 (2014), 753–761.
Goldstein, I., Yizhak, K., Madar, S., Goldfinger, N., Ruppin, E., Rotter, V., p53 promotes the expression of gluconeogenesis- related genes and enhances hepatic glucose production. Cancer & Metabolism, 1(1), 2013, 1.
Franck, D., Tracy, L., Armata, H.L., Delaney, C.L., Jung, D.Y., Ko, H.J., et al. Glucose tolerance in mice is linked to the dose of the p53 transactivation domain. Endocrine Research(3), 2012, 139–150.
Wang, X., Zhao, X., Gao, X., Mei, Y., Wu, M., A new role of p53 in regulating lipid metabolism. Journal of Molecular Cell Biology 5:2 (2013), 147–150.
Derdak, Z., Villegas, K.A., Harb, R., Wu, A.M., Sousa, A., Wands, J.R., Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. Journal of Hepatology 58:4 (2013), 785–791.
Bist, A., Fielding, C.J., Fielding, P.E., p53 regulates Caveolin gene transcription, cell cholesterol, and growth by a novel mechanism. Biochemistry 39:8 (2000), 1966–1972.
Krstic, J., Reinisch, I., Schupp, M., Schulz, T., Prokesch, A., p53 functions in adipose tissue metabolism and homeostasis. International Journal of Molecular Sciences, 19(9), 2018, 2622.
Bazuine, M., Stenkula, K.G., Cam, M., Arroyo, M., Cushman, S.W., Guardian of corpulence: a hypothesis on p53 signaling in the fat cell. Clinical Lipidology 4:2 (2009), 231–243.
Molchadsky, A., Shats, I., Goldfinger, N., Pevsner-Fischer, M., Olson, M., Rinon, A., et al. p53 plays a role in mesenchymal differentiation programs, in a cell fate dependent manner. PLoS One, 3(11), 2008, e3707.
Huang, Q., Liu, M., Du, X., Zhang, R., Xue, Y., Zhang, Y., et al. Role of p53 in preadipocyte differentiation. Cell Biology International 38:12 (2014), 1384–1393.
Okita, N., Ishikawa, N., Mizunoe, Y., Oku, M., Nagai, W., Suzuki, Y., et al. Inhibitory effect of p53 on mitochondrial content and function during adipogenesis. Biochemical and Biophysical Research Communications 446:1 (2014), 91–97.
Yahagi, N., Shimano, H., Matsuzaka, T., Najima, Y., Sekiya, M., Nakagawa, Y., et al. p53 activation in adipocytes of obese mice. Journal of Biological Chemistry 278:28 (2003), 25395–25400.
Molchadsky, A., Ezra, O., Amendola, P.G., Krantz, D., Kogan-Sakin, I., Buganim, Y., et al. p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity. Cell Death & Differentiation 20:5 (2013), 774–783.
Al-Massadi, O., Porteiro, B., Kuhlow, D., Köhler, M., Gonzalez-Rellan, M.J., Garcia-Lavandeira, M., et al. Pharmacological and genetic manipulation of p53 in Brown fat at adult but not embryonic stages regulates thermogenesis and body weight in male mice. Endocrinology 157:7 (2016), 2735–2749.
Kon, N., Wang, D., Li, T., Jiang, L., Qiang, L., Gu, W., Inhibition of Mdmx (Mdm4) in vivo induces anti-obesity effects. Oncotarget 9:7 (2018), 7282–7297.
Zhang, Y., Zeng, S.X., Hao, Q., Lu, H., Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner. Developmental Biology 423:1 (2017), 34–45.
Tornovsky-Babeay, S., Dadon, D., Ziv, O., Tzipilevich, E., Kadosh, T., Haroush, R.S.-B., et al. Type 2 diabetes and congenital hyperinsulinism cause DNA Double-strand breaksand p53 activity in b cells. Cell Metabolism 19:1 (2014), 109–121.
Hoshino, A., Ariyoshi, M., Okawa, Y., Kaimoto, S., Uchihashi, M., Fukai, K., et al. Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic-cell function in diabetes. Proceedings of the National Academy of Sciences 111:8 (2014), 3116–3121.
Kon, N., Zhong, J., Qiang, L., Accili, D., Gu, W., Inactivation of arf-bp1 induces p53 activation and diabetic phenotypes in mice. Journal of Biological Chemistry 287:7 (2012), 5102–5111.
Hinault, C., Kawamori, D., Liew, C.W., Maier, B., Hu, J., Keller, S.R., et al. Δ40 isoform of p53 controls cell proliferation and glucose homeostasis in mice. Diabetes 60:4 (2011), 1210–1222.
Li, X., Liu, Z., Yang, J.-K., Wang, B., Jiang, X., Zhou, Y., et al. The MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic. Nature Communications 7 (2016), 1–14.
Minamino, T., Orimo, M., Shimizu, I., Kunieda, T., Yokoyama, M., Ito, T., et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nature Medicine 15:9 (2009), 1–7.
Ortega, F.J., Moreno-Navarrete, J.M., Mayas, D., Serino, M., Rodriguez-Hermosa, J.I., Ricart, W., et al. Inflammation and insulin resistance exert dual effects on adipose tissue tumor protein 53 expression. International Journal of Obesity 38:5 (2014), 737–745.
Gaulton, K.J., Willer, C.J., Li, Y., Scott, L.J., Conneely, K.N., Jackson, A.U., et al. Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes. Diabetes 57:11 (2008), 3136–3144.
Burgdorf, K.S., Grarup, N., Justesen, J.M., Harder, M.N., Witte, D.R., Jørgensen, T., et al. Studies of the association of Arg72Pro of tumor suppressor protein p53 with type 2 diabetes in a combined analysis of 55,521 Europeans. PLoS One, 6(1), 2011, e15813.
Kung, C.-P., Leu, J.I.-J., Basu, S., Khaku, S., Anokye-Danso, F., Liu, Q., et al. The P72R polymorphism of p53 predisposes to obesity and metabolic dysfunction. Cell Reports 14:10 (2016), 2413–2425.
Yuan, H., Zhang, X., Huang, X., Lu, Y., Tang, W., Man, Y., et al. NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways. PLoS One, 5(12), 2010, e15726.
Vergoni, B., Cornejo, P.-J., Gilleron, J., Djedaini, M., Ceppo, F., Jacquel, A., et al. DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes. Diabetes 65:10 (2016), 3062–3074.
Secchiero, P., Toffoli, B., Melloni, E., Agnoletto, C., Monasta, L., Zauli, G., The MDM2 inhibitor Nutlin-3 attenuates streptozotocin-induced diabetes mellitus and increases serum level of IL-12p40. Acta Diabetologica 50:6 (2013), 899–906.
Yokoyama, M., Okada, S., Nakagomi, A., Moriya, J., Shimizu, I., Nojima, A., et al. Inhibition of endothelial p53 ImprovesMetabolic abnormalities related to dietary obesity. Cell Reports 7:5 (2014), 1691–1703.
Velasquez, D.A., Martinez, G., Romero, A., Vazquez, M.J., Boit, K.D., Dopeso-Reyes, I.G., et al. The central sirtuin 1/p53 pathway is essential for the orexigenic action of ghrelin. Diabetes 60:4 (2011), 1177–1185.
Farrell, G.C., Larter, C.Z., Hou, J.Y., Zhang, R.H., Yeh, M.M., Williams, J., et al. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. Journal of Gastroenterology and Hepatology 24:3 (2009), 443–452.
Tomita, K., Teratani, T., Suzuki, T., Oshikawa, T., Yokoyama, H., Shimamura, K., et al. p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. Journal of Hepatology 57:4 (2012), 837–843.
Panasiuk, A., Dzieciol, J., Panasiuk, B., Prokopowicz, D., Expression of p53, Bax and Bcl-2 proteins in hepatocytes in non-alcoholic fatty liver disease. World Journal of Gastroenterology 12:38 (2006), 6198–6202.
Kodama, T., Takehara, T., Hikita, H., Shimizu, S., Shigekawa, M., Tsunematsu, H., et al. Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice. Journal of Clinical Investigation 121:8 (2011), 3343–3356.
Porteiro, B., Fondevila, M.F., Buque, X., Gonzalez-Rellan, M.J., Fernandez, U., Mora, A., et al. Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis. Molecular Metabolism 8 (2018), 132–143.
Itahana, Y., Itahana, K., Emerging roles of p53 family members in glucose metabolism. International Journal of Molecular Sciences, 19(3), 2018, 776.
Candi, E., Smirnov, A., Panatta, E., Lena, A.M., Novelli, F., Mancini, M., et al. Metabolic pathways regulated by p63. Biochem Biophysic Res Commun 482:3 (2017), 440–444.
Napoli, M., Flores, E.R., The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy. British Journal of Cancer 116:2 (2016), 149–155.
Ruiz-Lozano, P., Hixon, M.L., Wagner, M.W., Flores, A.I., Ikawa, S., Badwin, A.S., et al. p53 is a transcriptional activator of the muscle-specific phosphoglycerate mutase gene and contributes in vivo to the control of its cardiac expression. Cell Growth & Differentiation 10:5 (1999), 295–306.
Mathupala, S.P., Heese, C., Pedersen, P.L., The type II of hehokinase promoter contains funcionally active response elements for the tumor suppressor p53. Journal of Biological Chemistry 272:36 (1997), 22776–22780.
Andrysik, Z., Galbraith, M.D., Guarnieri, A.L., Zaccara, S., Sullivan, K.D., Pandey, A., et al. Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity. Genome Research 27:10 (2017), 1645–1657.
Tan, M., Li, S., Swaroop, M., Guan, K., Oberley, L.W., Sun, Y., Transcriptional activation of the human glutathione peroxidase promoter by p53. Journal of Biological Chemistry 274:17 (1999), 12061–12066.
Lehar, S.M., Nacht, M., Jacks, T., Vater, C.A., Chittenden, T., Guild, B.C., Identification and cloning of EI24, a gene induced by p53 in etoposide-treated cells. Oncogene 12:6 (1996), 1181–1187.
